Expression analysis of BMP7 responsive P2RY1/ALK3 expressing progenitor like cells within the human exocrine pancreas
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ABSTRACT:
PROVIDER: PRJNA408303 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6058080_1.fastq.gz | Fastqsanger.gz | |||
| SRR6058080_2.fastq.gz | Fastqsanger.gz | |||
| SRR6058081_1.fastq.gz | Fastqsanger.gz | |||
| SRR6058081_2.fastq.gz | Fastqsanger.gz | |||
| SRR6058082_1.fastq.gz | Fastqsanger.gz |
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Project description:Purpose: Here we demonstrate ALK3Bright/PDX1+ cells residing within the human pancreatic ducts have progenitor like characteristics. Using flow cytometery, live-cell sorting of ALK3bright/PDX1+ cells is possible using a surrogate surface marker for PDX1 (P2RY1). Treating ALK3bright/P2RY1+ cells with BMP7 results in their expansion. Later removal of BMP7 results in the differentiation of these cells to β-like cells. Here we compare the mRNA expression profiles of these three different cell types (in triplicate). Methods: mRNA profiles of ALK3Bright/P2RY1+ cells isolated from human non-endocrine pancreatic tissue, ALK3Bright/P2RY1+ cells treated with BMP7 and ALK3Bright/P2RY1+ cells differentiated to β-like cells after BMP7 removal were generated by deep sequencing, in triplicate, using Illumina HiSeq PE Cluster Kit v4 and Illumina HiSeq Flow Cell v4 with 50 nt paired end reads plus dual index reads using the Illumina HiSeq SBS kit v4. Sequence reads that passed quality filters were analyzed at the transcript isoform level following alignment using TopHat v2.1.0 followed by exon and gene level counting using Bioconductor easyRNASeq v 2.4.7. Conclusions: Our study represents the first detailed analysis of ALK3Bright/P2RY1+ sorted cells with biological replicates. We demonstrate ALK3Bright/P2RY1+ cells were shown to form progenitor-like epithelial colonies characterized by NKX6.1 and PDX1 expression. Unlike the negative fraction controls, these colonies responded to BMP-7 by generating new β-like cells as well as cells from other pancreatic lineages. The transcriptional profile of these cells and their BMP7 treated counterparts suggest a mitotic and progenitor like state. Our studies confirm the progenitor-like nature of ALK3Bright/PDX1+ cells within the human pancreas and suggest a specific anatomical location within the ductal network.
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2011-12-09 | E-GEOD-34296 | biostudies-arrayexpress
Project description:We have determined the cistrome and transcriptome for the nuclear receptor liver receptor homolog-1 (LRH-1) in the exocrine pancreas. Chromatin immunoprecipitation (ChIP)-seq and RNA-seq analyses reveal that LRH-1 directly induces expression of genes encoding digestive enzymes and secretory and mitochrondrial proteins. LRH-1 cooperates with the pancreas transcription factor 1-L complex (PTF1-L) in regulationg exocrine pancreas-specific gene expression. Elimination of LRH-1 in adult mice reduced the concentration of several lipases and proteases in pancreatic fluid and impaired pancreatic fluid secretion in response to cholecystokinin. Thus, LRH-1 is a key regulator of the exocrine pancreas-specific transcriptional network required for the production and secretion of pancreatic fluid. input and Lrh1 ChIP
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Project description:We have determined the cistrome and transcriptome for the nuclear receptor liver receptor homolog-1 (LRH-1) in the exocrine pancreas. Chromatin immunoprecipitation (ChIP)-seq and RNA-seq analyses reveal that LRH-1 directly induces expression of genes encoding digestive enzymes and secretory and mitochrondrial proteins. LRH-1 cooperates with the pancreas transcription factor 1-L complex (PTF1-L) in regulationg exocrine pancreas-specific gene expression. Elimination of LRH-1 in adult mice reduced the concentration of several lipases and proteases in pancreatic fluid and impaired pancreatic fluid secretion in response to cholecystokinin. Thus, LRH-1 is a key regulator of the exocrine pancreas-specific transcriptional network required for the production and secretion of pancreatic fluid.
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Project description:Several miRNAs have tissue-specific patterns consistent with crucial functions in many biological processes and are candidate biomarkers of disease. Yet, there is limited knowledge about the role of pancreas-specific miRNAs in pancreatic pathologies. Here, we show that miR-216a is a conserved, pancreas-specific miRNA with important roles in pancreatic islet and acinar cells. By profiling miRNAs from human islets and subsequent systematic tissue analysis we found that miR-216a is highly enriched in endocrine and exocrine pancreas. Deletion of miR-216a in mice lead to a reduction in islet size, β-cell mass and insulin levels. RNA-sequencing indicated that cell cycle and proliferation were the most significantly regulated biological processes in miR-216 knockout pancreata. miR-216a was induced by TGF-β signalling and inhibition of miR-216a increased apoptosis and decreased cell proliferation in both β- and exocrine cells. Deletion of miR-216a in the pancreatic cancer prone mouse line Kras G12D ;Ptf1a CreER reduced the propensity of pancreatic cancer precursor lesions. Notably, circulating miR-216a levels were elevated in both mice and humans with pancreatic cancer. Collectively, our study gives insights into how β-cell mass and acinar cell growth are modulated by a pancreas-specific miRNA but also suggests miR-216a as a promising biomarker for diagnosis of pancreatic diseases.
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Project description:Purpose: We demonstrate here that human pancreatic ductal cells within the exocrine pancreas have multiple cell type populations. Flow cytometry and live-cell sorting of ALK3bright+ cells enabled transcriptomics analysis at the single cell level. Methods: Live CD90-/ALK3bright+ cells from 3 non-diabetic human donors were sorted and cryopreserved. After cryopreservation and dead cell removal, we performed single-cell cDNA library construction using the 10X Genomics microfluidics platform, utilizing the chromium single cell 3’ v2 chemistry kit. Single cell libraries were sequenced on an Illumina sequencing platform with 10X Genomics recommended parameters. After sequencing, data was converted to filtered read counts via the 10X Genomics Cellranger v3.0.2 software. Filtered gene counts were then utilized for downstream analysis using the Seurat scRNAseq analysis package. Conclusions: Our research presents the first detailed analysis at the single-cell level of ALK3-expressing ductal cells isolated from the human exocrine pancreas. This study reveals heterogeneity across the human ductal compartment, with certain sub-populations of ductal cells exhibiting progenitor-like characteristics. These data also demonstrate plasticity across the exocrine pancreas, which is donor-dependent. Overall, this study furthers our understanding of pancreatic biology at the single cell level.
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