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ENTPD3 Marks Mature Stem Cell Derived Beta Cells Formed by Self-Aggregation in Vitro

ABSTRACT: ENTPD3 Marks Mature Stem Cell Derived Beta Cells Formed by Self-Aggregation in Vitro

PROVIDER: PRJNA596473 | ENA |

REPOSITORIES: ENA

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ENTPD3 Marks Mature Stem Cell Derived Beta Cells Formed by Self-Aggregation in Vitro

Project description:Stem cell derived beta-like cells (sBC) carry the promise of providing an abundant source of insulin-producing cells for use in cell replacement therapy for patients with diabetes, potentially allowing widespread implementation of a practical cure. To achieve their clinical promise, sBC need to function comparably to mature adult beta cells, but as yet they display varying degrees of maturity. Indeed, detailed knowledge of the events resulting in human beta cell maturation remains obscure. Here we show that sBC spontaneously self-enrich into discreet islet-like cap structures within in vitro cultures, independent of exogenous maturation conditions. Multiple complementary assays demonstrate that this process is accompanied by functional maturation of the selfenriched sBC (seBC); however, the seBC still contain distinct subpopulations displaying different maturation levels. Interestingly, the surface protein ENTPD3 (also known as nucleoside triphosphate diphosphohydrolase-3 (NDPTase3)) is a specific marker of the most mature seBC population and can be used for mature seBC identification and sorting. Our results illuminate critical aspects of in vitro sBC maturation and provide important insights towards developing functionally mature sBC for diabetes cell replacement therapy.

2021-10-12 | GSE142290 | GEO

ENTPD3 Marks Mature Stem Cell Derived Beta Cells Formed by Self-Aggregation <i>in Vitro</i>.

Project description: Not available

| S-EPMC8564403 | biostudies-literature

Aggregation of respiratory complex subunits marks the onset of proteotoxicity in proteasome inhibited cells

Project description:Proteostasis is maintained by optimum expression, folding, transport, and clearance of proteins. Deregulation of any of these processes triggers protein aggregation and is implicated in many age-related pathologies. Here, using quantitative proteomics and microscopy we show that aggregation of many nuclear-encoded mitochondrial proteins is an early protein-destabilization event during short-term proteasome inhibition. Among these, Respiratory Chain Complex (RCC) subunits represent a group of functionally related proteins consistently forming aggregates under multiple proteostasis-stresses with varying aggregation-propensities. Sequence analysis reveals that several RCC subunits, irrespective of cleavable mitochondrial targeting sequence (MTS), contain low complexity regions (LCR) at N-terminus. Using different chimeric and mutant constructs we show that these low complexity regions partially contribute to intrinsic instability of multiple RCC subunits. Taken together, we propose that physicochemically driven aggregation of unassembled RCC subunits destabilizes their functional assembly inside mitochondria. This deregulates the biogenesis of respiratory complexes and marks the onset of mitochondrial dysfunction.

2019-01-28 | PXD012204 | Pride

Silk scaffolding drives self-assembly of functional and mature human brain organoids

Project description:Silk scaffolding drives self-assembly of functional and mature human brain organoids

| PRJNA804881 | ENA

Silk scaffolding drives self-assembly of functional and mature human brain organoids

Project description:Silk scaffolding drives self-assembly of functional and mature human brain organoids

| PRJNA837977 | ENA

RNA-DNA hybrids formed in the absence of Senataxin drive non-coding RNA expression and protein aggregation in the nucleolus

Project description:Neurodegeneration in the human population is often associated with loss of protein homeostasis that is driven by accumulation of specific aggregated proteins. Here we investigate whether deficiency in Senataxin, an RNA-DNA helicase associated with cerebellar ataxia and ALS, induces destabilization of intrinsically disordered proteins as we previously found with Ataxia-telangiectasia (A-T) cells and tissue. We find that Senataxin loss does generate protein aggregates but, unlike in A-T, these are associated with the nucleolus and are independent of oxidative stress and PARP activity. Non-coding RNA expression from the intergenic spacer region of ribosomal DNA is induced in the absence of Senataxin and drives the association and aggregation of many proteins known to be prone to aggregation in neurodegenerative disease. Both non-coding RNAs and protein aggregates are eliminated by overexpression of RNaseH1, implicating RNA-DNA hybrids as the key driver of these outcomes. We find that hybrids are high in the absence of Senataxin at intergenic sites, not at annotated protein-coding genes; these include sites of Senataxin binding in the genome, ribosomal DNA, and peri-centromeric regions. These findings suggest that destabilization of the proteome is driven by Senataxin loss and that RNA-DNA hybrids and non-coding RNAs play a critical role in this process.

2024-05-06 | GSE240664 | GEO

Silk scaffolding drives self-assembly of functional and mature human brain organoids [RNA-seq]

Project description:Silk scaffolding drives self-assembly of functional and mature human brain organoids [RNA-seq]

| PRJNA837980 | ENA

Transcription profiling of generic impact of protein aggregation (aggregation of proteins not associated with neurodegenerative disease) on gene expression in human cultured cells

Project description:In this study the generic impact of protein aggregation (aggregation of proteins not associated with neurodegenerative disease) on gene expression in cultured cells was investigated by DNA microarray technology. The survey of gene expression showed that the Hsp40, Hsp70 and Hsp105 genes, all of which have documented aggregation suppression activity, were up-regulated. Unexpectedly, the survey also showed increased expression of the MEK5 gene with concomitant silencing of the MEK3 gene. The expression pattern of MEK5 at the mRNA and protein levels aligns with the kinetics of aggregate formation and dissolution. Cell viability was unaffected by protein aggregates. These findings are of particular importance for chronic neurodegenerative diseases where the intraneuronal accumulation of aggregate-prone proteins are a major characteristic of the diseases. The identification of changes in MEK5 gene expression have been observed in Alzheimer-related diseases which provides new diagnostic and therapeutic avenues in these diseases. The molecular neuropathological findings would not have occurred without the generic microarray analyses.

2005-07-20 | E-MEXP-389 | biostudies-arrayexpress

Elucidating the molecular determinants of Aβ aggregation with deep mutational scanning

Project description:Despite the importance of Aβ aggregation in Alzheimer’s disease etiology, our understanding of the sequence determinants of aggregation is sparse and largely derived from in vitro studies. For example, in vitro proline and alanine scanning mutagenesis of Aβ40 proposed core regions important for aggregation. However, we lack even this limited mutagenesis data for the more disease-relevant Aβ42. Thus, to better understand the molecular determinants of Aβ42 aggregation in a cell-based system, we combined a yeast DHFR aggregation assay with deep mutational scanning. We measured the effect of 791 of the 798 possible single amino acid substitutions on the aggregation propensity of Aβ42. We found that ~75% of substitutions, largely to hydrophobic residues, maintained or increased aggregation. We identified 11 positions at which substitutions, particularly to hydrophilic and charged amino acids, disrupted Aβ aggregation. These critical positions were similar but not identical to critical positions identified in previous Aβ mutagenesis studies. Finally, we analyzed our large-scale mutagenesis data in the context of different Aβ aggregate structural models, finding that the mutagenesis data agreed best with models derived from fibrils seeded using brain-derived Aβ aggregates.

2019-10-21 | GSE139122 | GEO

Nucleosomal chromatin in the mature sperm of Drosophila melanogaster.

Project description:Nucleosomal chromatin persists in the mature sperm of Drosophila melanogaster. Paternal epigenetic marks of repression and active transcription are found within many genes essential for embryogenesis. These marks are delivered at fertilization and are subsequently maintained in the early embryo.

2015-09-30 | GSE52165 | GEO

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