Dataset Information

Neuroprotective Activities of Heparin, Heparinase III, and Hyaluronic Acid on the A?42-Treated Forebrain Spheroids Derived from Human Stem Cells.

ABSTRACT: Extracellular matrix (ECM) components of the brain play complex roles in neurodegenerative diseases. The study of microenvironment of brain tissues with Alzheimer's disease revealed colocalized expression of different ECM molecules such as heparan sulfate proteoglycans (HSPGs), chondroitin sulfate proteoglycans (CSPGs), matrix metal-loproteinases (MMPs), and hyaluronic acid. In this study, both cortical and hippocampal populations were generated from human-induced pluripotent stem cell-derived neural spheroids. The cultures were then treated with heparin (competes for A? affinity with HSPG), heparinase III (digests HSPGs), chondroitinase (digests CSPGs), hyaluronic acid, and an MMP-2/9 inhibitor (SB-3CT) together with amyloid ? (A?42) oligomers. The results indicate that inhibition of HSPG binding to A?42 using either heparinase III or heparin reduces A?42 expression and increases the population of ?-tubulin III+ neurons, whereas the inhibition of MMP2/9 induces more neurotoxicity. The results should enhance our understanding of the contribution of ECMs to the A?-related neural cell death.

SUBMITTER: Bejoy J

PROVIDER: S-EPMC6286050 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Neuroprotective Activities of Heparin, Heparinase III, and Hyaluronic Acid on the A<i>β</i>42-Treated Forebrain Spheroids Derived from Human Stem Cells.

Bejoy Julie J Song Liqing L Wang Zhe Z Sang Qing-Xiang QX Zhou Yi Y Li Yan Y

ACS biomaterials science & engineering 20180628 8

Extracellular matrix (ECM) components of the brain play complex roles in neurodegenerative diseases. The study of microenvironment of brain tissues with Alzheimer's disease revealed colocalized expression of different ECM molecules such as heparan sulfate proteoglycans (HSPGs), chondroitin sulfate proteoglycans (CSPGs), matrix metal-loproteinases (MMPs), and hyaluronic acid. In this study, both cortical and hippocampal populations were generated from human-induced pluripotent stem cell-derived n ...[more]

PMID: 30533518

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Project description:Extracellular vesicles (EVs) secreted by human brain cells have great potential as cell-free therapies in various diseases, including stroke. However, because of the significant amount of EVs needed in preclinical and clinical trials, EV application is still challenging. Vertical-Wheel Bioreactors (VWBRs) have designed features that allow for scaling up the generation of human forebrain spheroid EVs under low shear stress. In this study, EV secretion by human forebrain spheroids derived from induced pluripotent stem cells as 3D aggregates and on Synthemax II microcarriers in VWBRs were investigated with static aggregate culture as a control. The spheroids were characterized by metabolite and transcriptome analysis. The isolated EVs were characterized by nanoparticle tracking analysis, electron microscopy, and Western blot. The EV cargo was analyzed using proteomics and miRNA sequencing. The in vitro functional assays of an oxygen and glucose-deprived stroke model were conducted. Proof of concept in vivo study was performed, too. Human forebrain spheroid differentiated on microcarriers showed a higher growth rate than 3D aggregates. Microcarrier culture had lower glucose consumption per million cells and lower glycolysis gene expression but higher EV biogenesis genes. EVs from the three culture conditions showed no differences in size, but the yields from high to low were microcarrier cultures, dynamic aggregates, and static aggregates. The cargo is enriched with proteins (proteomics) and miRNAs (miRNA-seq), promoting axon guidance, reducing apoptosis, scavenging reactive oxygen species, and regulating immune responses. Human forebrain spheroid EVs demonstrated the ability to improve recovery in an in vitro stroke model and in vivo. Human forebrain spheroid differentiation in VWBR significantly increased the EV yields (up to 240-750 fold) and EV biogenesis compared to static differentiation due to the dynamic microenvironment and metabolism change. The biomanufactured EVs from VWBRs have exosomal characteristics and more therapeutic cargo and are functional in in vitro assays, which paves the way for future in vivo stroke studies.

Dataset Information

Neuroprotective Activities of Heparin, Heparinase III, and Hyaluronic Acid on the A?42-Treated Forebrain Spheroids Derived from Human Stem Cells.

Publications

Neuroprotective Activities of Heparin, Heparinase III, and Hyaluronic Acid on the A<i>β</i>42-Treated Forebrain Spheroids Derived from Human Stem Cells.

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