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Robust Expansion of Human Pancreatic Progenitors by Small Molecules [ChIP-seq]

ABSTRACT: An unlimited source of functional human pancreatic β cells are in highly demand. Even with recent advances in pancreatic β-like cell differentiation from human pluripotent stem cells (hPSCs), several hurdles obviously remain and the differentiation protocols need to be further improved. Chemical strategies are particularly useful to address these challenges. Here, through chemical screening, we unexpectedly identified that BET bromodomain inhibitor I-BET151 could robustly promote the expansion of PDX1 and NKX6.1 double-positive human pancreatic progenitors (PPs). These hPSC-derived expandable pancreatic progenitors (ePPs) can proliferate extensively in a chemically defined condition with I-BET151. Even after long-term expansion, these ePPs maintain pancreatic progenitor cell status. In addition, ePPs can efficiently differentiate into pancreatic β-like cells (ePP-β cells). These ePP-β cells are functional and demonstrate glucose-stimulation insulin-secretion (GSIS) capacity. Mechanistically, I-BET151 can activate Notch signaling and promote the expression of key pancreatic progenitor-associated genes and transcriptional network. Conclusively, our studies achieve the long-term goal of robust expansion of human pancreatic progenitors and represent a significant step towards unlimited supplies of functional human pancreatic β cells that are of great interest for biomedical research and regenerative medicine.

ORGANISM(S): Homo sapiens

PROVIDER: GSE156710 | GEO | 2022/02/24

REPOSITORIES: GEO

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Robust Expansion of Human Pancreatic Progenitors by Small Molecules [ATAC-seq]

Project description:An unlimited source of functional human pancreatic β cells are in highly demand. Even with recent advances in pancreatic β-like cell differentiation from human pluripotent stem cells (hPSCs), several hurdles obviously remain and the differentiation protocols need to be further improved. Chemical strategies are particularly useful to address these challenges. Here, through chemical screening, we unexpectedly identified that BET bromodomain inhibitor I-BET151 could robustly promote the expansion of PDX1 and NKX6.1 double-positive human pancreatic progenitors (PPs). These hPSC-derived expandable pancreatic progenitors (ePPs) can proliferate extensively in a chemically defined condition with I-BET151. Even after long-term expansion, these ePPs maintain pancreatic progenitor cell status. In addition, ePPs can efficiently differentiate into pancreatic β-like cells (ePP-β cells). These ePP-β cells are functional and demonstrate glucose-stimulation insulin-secretion (GSIS) capacity. Mechanistically, I-BET151 can activate Notch signaling and promote the expression of key pancreatic progenitor-associated genes and transcriptional network. Conclusively, our studies achieve the long-term goal of robust expansion of human pancreatic progenitors and represent a significant step towards unlimited supplies of functional human pancreatic β cells that are of great interest for biomedical research and regenerative medicine.

2022-02-24 | GSE156711 | GEO

Robust Expansion of Human Pancreatic Progenitors by Small Molecules [RNA-seq]

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TEAD and YAP regulate the enhancer network of human embryonic pancreatic progenitors

Project description:The genomic regulatory programs that underlie human organogenesis are poorly understood. Human pancreas development, in particular, has pivotal implications for pancreatic regeneration, cancer, and diabetes. We have now created maps of transcripts, active enhancers, and transcription factor networks in pancreatic multipotent progenitors obtained from human embryos, or derived in vitro from human embryonic stem cells. This revealed that artificial progenitors recapitulate salient transcriptional and epigenomic features of their natural counterparts. Using this resource, we show that TEAD1, a transcription factor controlled by Hippo signaling, is a core component of the combinatorial code of pancreatic progenitor enhancers. TEAD thus activates genes encoding regulators of signaling pathways and stage-specific transcription factors that are essential for normal pancreas development. Accordingly, chemical and genetic perturbations of TEAD and its coactivator YAP inhibited expression of known regulators such as FGFR2 and SOX9, and suppressed the proliferation and expansion of mouse and zebrafish pancreatic progenitors. These findings provide a resource of active enhancers and transcripts in human pancreatic multipotent progenitors, and uncover a central role of TEAD and YAP as signal-responsive regulators of the transcriptional program of early pancreas development.

2015-04-06 | E-MTAB-3061 | biostudies-arrayexpress

Expression DATA from E11.5 pancreatic buds treated with I-BET151 or JQ1 for 24h

Project description:Bromodomain and Extra-terminal (BET) proteins are epigenetic readers that interact with acetylated lysines of histone tails. Recent studies have demonstrated their role in cancer progression, as they recruit key components of the transcriptional machinery to modulate gene expression. However, their role during embryonic development of the pancreas has never been studied. Using mouse embryonic pancreatic explants and human IPSC, we show that inhibition of BET proteins with either I-BET151 or JQ1 dramatically enhances the number of neurogenin3 (NEUROG3) endocrine progenitors, leading to an increased number of endocrine cells in the pancreatic explants. Despite inducing several β cell markers, BETi also strongly down-regulated Ins1 expression in developed explants and adult β cells. However, removal of BETi from explants prior to β cell development, as NEUROG3 expression peaks, further led to enhanced β cell development with higher expression of insulin and maturation markers UCN3 and MAFA. Altogether, these results show that BET proteins play a major role in the pancreas endocrine differentiation. Furthermore, they highlight the potential use of BETi to improve β cell replacement therapies.

2020-01-01 | GSE109858 | GEO

A conditionally immortalized human pancreatic beta cell line

Project description:Access to an unlimited number of human pancreatic beta cells represents a major challenge in the field of diabetes to better dissect human beta cell functions and to make significant progress in drug discovery and cell replacement therapies. We previously reported the generation of the EndoC-bH1 human beta cell line that was generated by targeted oncogenesis in human fetal pancreases followed by in vivo cell differentiation in mice. Such cell line displayed many functional properties of adult beta cells. Here we devised a novel strategy to generate conditionally immortalized human beta cell lines based on CRE-mediated excision of immortalizing transgenes. The resulting EndoC-bH2 cell line can be massively amplified in vitro. Transgenes are next efficiently excised upon CRE expression leading to cell proliferation arrest and strong enhancement of beta cell specific features such as insulin expression, content and secretion. Excised EndoC-bH2 cells are close to authentic human beta cells and represent a unique tool to further study beta cell function and to understand why adult human beta cells are refractory to proliferation and how to achieve drug-dependent mobilization towards beta cell expansion. Expression profile of human beta cell lineEndoC-bH2 before and after excision of an immortalization cassette (SV40 LT and hTERT) is compared to human exocrine pancreas cell line SKPC and adult human islets from cadaveric donors. Three replicates were used for each sample group. The three adult human islets samples were taken from GEO series GSE40709 (GSM999550, GSM999551 and GSM999552) and normalized with H357 and SKPC cell line samples using RMA.

2014-03-21 | E-GEOD-48101 | biostudies-arrayexpress

A conditionally immortalized human pancreatic beta cell line

2014-03-21 | GSE48101 | GEO

Transcriptome analysis of self-renewing human pancreatic progenitors derived from pluripotent stem cells

Project description:Human pluripotent stem cells were differentiated into PDX1+/NKX6-1+ Pancreatic Progenitors (PPd15 cells), which were subsequently captured and expanded in culture. These culture Pancreatic Progenitors (cPP cells) were capable of self-renewal and could be passaged up to 20 times. Furthermore, cPP cells were capable of differentiation into multiple pancreatic lineages, including c-peptide+ beta-like cells, both in vitro and in vivo.

2017-06-06 | E-MTAB-5731 | biostudies-arrayexpress

Transcriptome profiling of human pancreatic cell lineage specification reveals functional signaling pathways and lncRNAs for cell fate determination

Project description:To guide the beta cell differentiation process in vitro, a complete understanding of the transcriptome and their regulatory network during the differentiation process is essential. Using RNA-seq, we have performed the transcriptome profiling of human embryonic stem cells (ESCs), purified ESC-derivate definitive endoderm (DE), pancreatic progenitors (PP), as well as sorted human primary pancreatic alpha cells, beta cells and exocrine cells.

2016-02-20 | E-MTAB-3356 | biostudies-arrayexpress

microRNA and mRNA expression profiles of human pancreatic islet-like cell clusters

Project description:Type 1 diabetes is an autoimmune destruction of pancreatic islet beta cell disease, and it is important to find new alternative source of the islet beta cells to replace the damaged cells. Human embryonic stem (hES) cells possess unlimited self-renewal and pluripotency and thus have the potential to provide an unlimited supply of different cell types for tissue replacement. The hES-T3 cells with normal female karyotype were first differentiated into embryoid bodies and then induced to generate the pancreatic islet-like cell clusters, which expressed pancreatic islet cell-specific markers of insulin, glucagon and somatostatin. The expression profiles of microRNAs and mRNAs from the pancreatic islet-like cell clusters were further analyzed and compared with those of undifferentiated hES-T3 cells and differentiated embryoid bodies. MicroRNAs negatively regulate the expression of protein-coding mRNAs. The pancreatic islet-like cell clusters were found to exhibit very high expression of microRNAs miR-186, miR-199a and miR-339, which down-regulated the expression of LIN28, PRDM1, CALB1, GCNT2, RBM47, PLEKHH1, RBPMS2 and PAK6. Therefore, these microRNAs are very likely to play important regulatory roles in the differentiation of pancreatic islet cells and early embryonic development. In this investigation, both miRNA and mRNA expression profiles from the pancreatic islet-like cell clusters differentiated from hES-T3 cells (T3pi) were quantitatively determined and compared with those of undifferentiated hES-T3 cells grown on mouse embryonic fibroblast (MEF) feeder (T3ES) and embryoid bodies differentiated from hES-T3 cells (T3EB). Several target genes of pancreatic islet cell-specific miRNAs were identified. ***This submission represents the mRNA expression component of the study only***

2010-09-29 | E-GEOD-14503 | biostudies-arrayexpress

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