Characterization and reduction of non-endocrine cells accompanying islet-like endocrine cells differentiated from human iPSC
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE213290 | GEO | 2022/09/16
REPOSITORIES: GEO
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Project description:MicroRNAs (miRNAs) are small non-coding RNA molecules that have the ability to drive cell lineage decisions by regulating the expression of hundreds of genes. Although evidence indicates that miRNAs have roles in pancreas development and endocrine cell function, the role of miRNAs in pancreatic endocrine cell differentiation has not been systematically explored. To address this, we performed genome-wide small RNA sequencing analysis in pancreatic progenitor cells differentiated in vitro from human embryonic stem cells and endocrine cells isolated from whole human islets. This analysis revealed miRNAs that increase in expression during endocrine cell differentiation. Employing gain-of-function experiments, we identified four miRNAs that can repress a large number of genes that are normally down-regulated during endocrine cell differentiation, including genes encoding transcription factors known to regulate endocrine cell development as well as cell cycle regulators. This knowledge about miRNA target genes in conjunction with HITS-CLIP data allowed us to construct an integrated miRNA-gene regulatory network of endocrine cell differentiation. Our integrated analysis indicates a key role for the identified miRNAs in establishing a transcriptional landscape that promotes the differentiation of pancreatic progenitor cells into endocrine cells. This study not only sheds light on the mechanisms that underlie human endocrine cell differentiation, but also has important implications for devising improved protocols for producing replacement beta cells for diabetes cell therapy.
2019-11-14 | GSE115326 | GEO
Project description:MicroRNAs (miRNAs) are small non-coding RNA molecules that have the ability to drive cell lineage decisions by regulating the expression of hundreds of genes. Although evidence indicates that miRNAs have roles in pancreas development and endocrine cell function, the role of miRNAs in pancreatic endocrine cell differentiation has not been systematically explored. To address this, we performed genome-wide small RNA sequencing analysis in pancreatic progenitor cells differentiated in vitro from human embryonic stem cells and endocrine cells isolated from whole human islets. This analysis revealed miRNAs that increase in expression during endocrine cell differentiation. Employing gain-of-function experiments, we identified four miRNAs that can repress a large number of genes that are normally down-regulated during endocrine cell differentiation, including genes encoding transcription factors known to regulate endocrine cell development as well as cell cycle regulators. This knowledge about miRNA target genes in conjunction with HITS-CLIP data allowed us to construct an integrated miRNA-gene regulatory network of endocrine cell differentiation. Our integrated analysis indicates a key role for the identified miRNAs in establishing a transcriptional landscape that promotes the differentiation of pancreatic progenitor cells into endocrine cells. This study not only sheds light on the mechanisms that underlie human endocrine cell differentiation, but also has important implications for devising improved protocols for producing replacement beta cells for diabetes cell therapy.
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Project description:MicroRNAs (miRNAs) are small non-coding RNA molecules that have the ability to drive cell lineage decisions by regulating the expression of hundreds of genes. Although evidence indicates that miRNAs have roles in pancreas development and endocrine cell function, the role of miRNAs in pancreatic endocrine cell differentiation has not been systematically explored. To address this, we performed genome-wide small RNA sequencing analysis in pancreatic progenitor cells differentiated in vitro from human embryonic stem cells and endocrine cells isolated from whole human islets. This analysis revealed miRNAs that increase in expression during endocrine cell differentiation. Employing gain-of-function experiments, we identified four miRNAs that can repress a large number of genes that are normally down-regulated during endocrine cell differentiation, including genes encoding transcription factors known to regulate endocrine cell development as well as cell cycle regulators. This knowledge about miRNA target genes in conjunction with HITS-CLIP data allowed us to construct an integrated miRNA-gene regulatory network of endocrine cell differentiation. Our integrated analysis indicates a key role for the identified miRNAs in establishing a transcriptional landscape that promotes the differentiation of pancreatic progenitor cells into endocrine cells. This study not only sheds light on the mechanisms that underlie human endocrine cell differentiation, but also has important implications for devising improved protocols for producing replacement beta cells for diabetes cell therapy.
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Project description:MicroRNAs (miRNAs) are small non-coding RNA molecules that have the ability to drive cell lineage decisions by regulating the expression of hundreds of genes. Although evidence indicates that miRNAs have roles in pancreas development and endocrine cell function, the role of miRNAs in pancreatic endocrine cell differentiation has not been systematically explored. To address this, we performed genome-wide small RNA sequencing analysis in pancreatic progenitor cells differentiated in vitro from human embryonic stem cells and endocrine cells isolated from whole human islets. This analysis revealed miRNAs that increase in expression during endocrine cell differentiation. Employing gain-of-function experiments, we identified four miRNAs that can repress a large number of genes that are normally down-regulated during endocrine cell differentiation, including genes encoding transcription factors known to regulate endocrine cell development as well as cell cycle regulators. This knowledge about miRNA target genes in conjunction with HITS-CLIP data allowed us to construct an integrated miRNA-gene regulatory network of endocrine cell differentiation. Our integrated analysis indicates a key role for the identified miRNAs in establishing a transcriptional landscape that promotes the differentiation of pancreatic progenitor cells into endocrine cells. This study not only sheds light on the mechanisms that underlie human endocrine cell differentiation, but also has important implications for devising improved protocols for producing replacement beta cells for diabetes cell therapy.
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Project description:MicroRNAs (miRNAs) are small non-coding RNA molecules that have the ability to drive cell lineage decisions by regulating the expression of hundreds of genes. Although evidence indicates that miRNAs have roles in pancreas development and endocrine cell function, the role of miRNAs in pancreatic endocrine cell differentiation has not been systematically explored. To address this, we performed genome-wide small RNA sequencing analysis in pancreatic progenitor cells differentiated in vitro from human embryonic stem cells and endocrine cells isolated from whole human islets. This analysis revealed miRNAs that increase in expression during endocrine cell differentiation. Employing gain-of-function experiments, we identified four miRNAs that can repress a large number of genes that are normally down-regulated during endocrine cell differentiation, including genes encoding transcription factors known to regulate endocrine cell development as well as cell cycle regulators. This knowledge about miRNA target genes in conjunction with HITS-CLIP data allowed us to construct an integrated miRNA-gene regulatory network of endocrine cell differentiation. Our integrated analysis indicates a key role for the identified miRNAs in establishing a transcriptional landscape that promotes the differentiation of pancreatic progenitor cells into endocrine cells. This study not only sheds light on the mechanisms that underlie human endocrine cell differentiation, but also has important implications for devising improved protocols for producing replacement beta cells for diabetes cell therapy.
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Project description:MicroRNAs (miRNAs) are small non-coding RNA molecules that have the ability to drive cell lineage decisions by regulating the expression of hundreds of genes. Although evidence indicates that miRNAs have roles in pancreas development and endocrine cell function, the role of miRNAs in pancreatic endocrine cell differentiation has not been systematically explored. To address this, we performed genome-wide small RNA sequencing analysis in pancreatic progenitor cells differentiated in vitro from human embryonic stem cells and endocrine cells isolated from whole human islets. This analysis revealed miRNAs that increase in expression during endocrine cell differentiation. Employing gain-of-function experiments, we identified four miRNAs that can repress a large number of genes that are normally down-regulated during endocrine cell differentiation, including genes encoding transcription factors known to regulate endocrine cell development as well as cell cycle regulators. This knowledge about miRNA target genes in conjunction with HITS-CLIP data allowed us to construct an integrated miRNA-gene regulatory network of endocrine cell differentiation. Our integrated analysis indicates a key role for the identified miRNAs in establishing a transcriptional landscape that promotes the differentiation of pancreatic progenitor cells into endocrine cells. This study not only sheds light on the mechanisms that underlie human endocrine cell differentiation, but also has important implications for devising improved protocols for producing replacement beta cells for diabetes cell therapy.
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Project description:During pancreatic development, Neurogenin3 (Ngn3) promotes the differentiation of endocrine cells, including insulin-producing β-cells. Our previous work has shown that Ngn3 phosphorylation on multiple serine-proline (SP) sites increases protein stability and endocrine differentiation (Azzarelli et al., DevCell 2017). Here, we aim to exploit our recent data to investigate whether manipulation of Ngn3 phosphostatus might improve in vitro generation of β-cells for replacement therapies in diabetes. A potential source of β-cells comes from fate conversion of exocrine pancreatic cells into the endocrine lineage, by overexpression of 3 transcription factors, Ngn3, Pdx1 and MafA. Using this approach we show that pancreatic ductal cells grown in vitro as 3D organoids can be reprogrammed to express insulin. The efficiency can be strongly enhanced by substituting wild type Ngn3 with a the un(der)phosphorylated and more active Ngn3 form (6S-A Ngn3). Here we perform transcriptomic analysis of a low number of pancreatic organoid cells expressing wild type or phosphomutant Ngn3, alone or in various combination Pdx1 and/or MafA. The analysis revealed endocrine differentiation and in particular β-like cell gene expression in the conditions where Ngn3 was in combination with both Pdx1 and MafA.
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