Single cell RNA-Seq of adult mouse pancreatic stem cells and early progenitors
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus synthetic construct
PROVIDER: GSE110283 | GEO | 2019/09/10
REPOSITORIES: GEO
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Project description:Single cell RNA-Seq of adult mouse pancreatic stem cells and early progenitors
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Project description:The mitochondrial enzyme ALDH1B1 is upregulated in colorectal and pancreatic adenocarcinomas and promotes tumor growth. Using both genetic and chemical perturbations, we have characterized the ALDH1B1-regulated transcriptome in a colorectal cancer cell line. Genes induced by ALDH1B1 include those related to mitochondrial metabolism, stemness, and ribosomal function. These findings implicate ALDH1B1 in cancer metabolism and cancer stem cell maintenance, and they underscore the potential of ALDH1B1 as a therapeutic target.
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Project description:Pancreatic islet cells derived from human pluripotent stem cells hold great promise for modeling and treating diabetes. Differences between stem cell-derived and primary islets remain, but molecular insights to inform improvements are limited. Here, we acquire single-cell transcriptomes and accessible chromatin profiles during in vitro islet differentiation and from primary childhood and adult pancreas for comparison. We delineate major cell types, define their regulomes, and describe spatiotemporal regulatory relationships between transcription factors. CDX2 emerged as a regulator of enterochromaffin-like cells, which we show resemble a previously unrecognized, transient CDX2-expressing β-cell-related population in fetal pancreas, arguing against a non-pancreatic origin as proposed. Furthermore, we observe insufficient activation of signal-dependent transcriptional programs during in vitro β-cell maturation and identify sex hormones as drivers of childhood β-cell proliferation. Altogether, our analysis provides a comprehensive understanding of cell fate acquisition in stem cell-derived islets and a framework for manipulating cell identities and maturity.
2023-03-02 | GSE202491 | GEO
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Project description:Gene expression profiles from ALDH high cells sorted from expanded adult human pancreatic organoids are more similar to fetal pancreatic tissue and ALDH high cells sorted from expanded fetal human pancreatic organoids than to adult human islets or adult islet-depleted exocrine tissue.
2019-01-08 | GSE108854 | GEO
Project description:We report the transcriptome of single pancreatic cells at embryonic day e13.5
2016-12-27 | GSE78510 | GEO
Project description:Aims/hypothesis: Duct cells isolated from adult human pancreas can be reprogrammed to express islet beta cell genes by adenoviral transduction of the developmental transcription factor neurogenin3 (Ngn3). In this study we aimed to fully characterize the extent of this reprogramming and intended to improve it. Methods: The extent of the Ngn3-mediated duct-to-endocrine cell reprogramming was measured employing genome wide mRNA profiling. By modulation of the Delta-Notch signaling or addition of pancreatic endocrine transcription factors Myt1, MafA and Pdx1 we intended to improve the reprogramming. Results: Ngn3 stimulates duct cells to express a focused set of genes that are abundant in islet endocrine cells and/or neural tissues. This neuro-endocrine shift, however, covers a minor fraction (5%) of the estimated genome-wide transcriptome difference between duct and islet endocrine cells. Interestingly, transduction of exogenous Ngn3 activates endogenous Ngn3 suggesting auto-activation of this gene. Furthermore, pancreatic endocrine reprogramming of human duct cells can be moderately enhanced by inhibition of Delta-Notch signaling as well as by co-expressing the transcription factor Myt1, but not MafA and Pdx1. Conclusions/interpretation: The results provide further insight into the plasticity of adult human duct cells and suggest measurable routes to enhance Ngn3-mediated in vitro reprogramming protocols for regenerative beta cell therapy in diabetes. We used Affymetrix HG133A and HG133B to get a comprehensive view on the reprogramming potential in vitro of human pancreatic duct cell cultures (n=3-4) at 3 and 14/20 days after ectopic adenoviral expression of murine neurogenin 3 as compared to GFP-expressing control vectors.
2012-07-11 | GSE30802 | GEO
Project description:Aims/hypothesis Pancreatic beta cells maintain glucose homeostasis and beta cell dysfunction is a major risk factor in developing diabetes. Therefore, understanding the developmental regulatory networks that define a fully functional beta cell is important for elucidating the genetic origins of the disease. Aldehyde dehydrogenase activity has been associated with stem/progenitor cells and we have previously shown that Aldh1b1 is specifically expressed in pancreas progenitor pools. Here we address the hypothesis that Aldh1b1 may regulate the timing of the appearance and eventual functionality of beta cells. Methods We generated an Aldh1b1-knockout mouse line (Aldh1b1tm1lacZ) and used this to study pancreatic development, beta cell functionality and glucose homeostasis in the absence of Aldh1b1 function. Results Differentiation in the developing pancreas of Aldh1b1tm1lacZ null mice was accelerated. Transcriptome analyses of newborn and adult islets showed misregulation of key beta cell transcription factors and genes crucial for beta cell function. Functional analyses showed that glucose-stimulated insulin secretion was severely compromised in islets isolated from null mice. Several key features of beta cell functionality were affected, including control of oxidative stress, glucose sensing, stimulus-coupling secretion and secretory granule biogenesis. As a result of beta cell dysfunction, homozygous mice developed glucose intolerance and age-dependent hyperglycaemia. Conclusions/interpretation These findings show that Aldh1b1 influences the timing of the transition from the pancreas endocrine progenitor to the committed beta cell and demonstrate that changes in the timing of this transition lead to beta cell dysfunction and thus constitute a diabetes risk factor later in life.
2015-07-31 | GSE58025 | GEO
Project description:Aims/hypothesis: Duct cells isolated from adult human pancreas can be reprogrammed to express islet beta cell genes by adenoviral transduction of the developmental transcription factor neurogenin3 (Ngn3). In this study we aimed to fully characterize the extent of this reprogramming and intended to improve it. Methods: The extent of the Ngn3-mediated duct-to-endocrine cell reprogramming was measured employing genome wide mRNA profiling. By modulation of the Delta-Notch signaling or addition of pancreatic endocrine transcription factors Myt1, MafA and Pdx1 we intended to improve the reprogramming. Results: Ngn3 stimulates duct cells to express a focused set of genes that are abundant in islet endocrine cells and/or neural tissues. This neuro-endocrine shift, however, covers a minor fraction (5%) of the estimated genome-wide transcriptome difference between duct and islet endocrine cells. Interestingly, transduction of exogenous Ngn3 activates endogenous Ngn3 suggesting auto-activation of this gene. Furthermore, pancreatic endocrine reprogramming of human duct cells can be moderately enhanced by inhibition of Delta-Notch signaling as well as by co-expressing the transcription factor Myt1, but not MafA and Pdx1. Conclusions/interpretation: The results provide further insight into the plasticity of adult human duct cells and suggest measurable routes to enhance Ngn3-mediated in vitro reprogramming protocols for regenerative beta cell therapy in diabetes. We used Affymetrix HG133A and HG133B to get a comprehensive view on the reprogramming potential in vitro of human pancreatic duct cell cultures (n=3-4) at 3 and 14/20 days after ectopic adenoviral expression of murine neurogenin 3 as compared to GFP-expressing control vectors. The microarray analysis was performed on 3 independent samples that each contained RNA extracted from a pool of 3 independent donor pancreata. The total number of non-selected donor organs is 9. Transcripts were considered as differentially regulated by Ngn3 when 1.5 fold (LCB, unpaired P < 0.05) up- or down-regulated in AdGFP-Ngn3 versus AdGFP controls, at 3 and/or 14 dpi. Transcripts that showed differential expression between day 3 and day 14 in AdGFP-Ngn3 duct cells but not in AdGFP control cells, were also considered Ngn3-regulated
2012-07-10 | E-GEOD-30802 | biostudies-arrayexpress
Project description:After their destruction in adult mice, insulin-producing pancreatic beta-cells slowly regenerate from other islet cells, like glucagon-producing alpha-cells. However the molecular basis of this conversion is unknown. Moreover it remains unclear if this intra-islet cell conversion is relevant to human diseases with extensive beta-cell loss, like in type 1 diabetes (T1D). Here, we show that subsets of glucagon-expressing cells in subjects with T1D produce Insulin and other molecular features of beta-cells, accompanied by loss of the alpha-cell regulators DNA methyltransferase 1 (Dnmt1) and Aristaless-related homeobox (Arx). We generated mice permitting lineage tracing and inactivation of Dnmt1 and Arx in adult alpha-cells. Within 3 months of Dnmt1 and Arx loss, 50% of alpha-cells converted into cells producing insulin protein but not glucagon, changes not observed in alpha-cells after only Arx or Dnmt1 loss. Single cell isolation and high-throughput RNA sequencing revealed efficient and extensive alpha-cell conversion into progeny indistinguishable by global gene expression from native beta-cells. Our work reveals pathways regulated by Arx and Dnmt1 sufficient for achieving targeted generation of beta-cells from adult pancreatic alpha-cells.
2017-02-16 | GSE79457 | GEO