Charting a high-resolution roadmap for regeneration of pancreatic β cells by in vivo transdifferentiation from adult acinar cells
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE224572 | GEO | 2023/04/10
REPOSITORIES: GEO
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Project description:Charting a high-resolution roadmap for regeneration of pancreatic β cells by in vivo transdifferentiation from adult acinar cells
| PRJNA931764 | ENA
Project description:Pancreatic ductal adenocarcinoma (PDAC) is characterized by desmoplastic stroma surrounding most tumors. Activated stromal fibroblasts, namely Cancer-associated fibroblasts (CAFs), play a major role in PDAC progression. Here we analyzed if CAFs influence acinar cells and impact PDAC initiation, namely “Acinar to Ductal Metaplasia” (ADM). ADM connection with PDAC pathophysiology is indicated but not yet established. Hence, we hypothesized that CAF secretome might play a significant role in ADM in PDAC initiation. Mouse and human acinar cell organoids, acinar cells cocultured with CAFs and exposed to CAF-conditioned media (CAF-CM), acinar cell explants, and CAF cocultures, etc., were examined by qRT-PCR, RNA-seq, immunoblotting and confocal microscopy. Data from LC-MS/MS analysis of CAF CM and RNAseq data of acinar cells post-CM exposure were integrated using bioinformatics tools to identify molecular mechanism for CAF-induced ADM. Using confocal microscopy, immunoblotting, and qRT-PCR analysis, we validated the depletion of key signaling axis in cell-line, acinar explant coculture, and mCAFs. Close association of acino-ductal (UEA1, Amylase, Ck19) markers and mCAFs (α-SMA) in LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1Cre (KPC) and LSL-KrasG12D/+; Pdx1Cre (KC) autochthonous progression tumor tissue was observed. Caerulein treatment-induced mCAFs increased Ck19 and decreased Amylase in wild-type (WT) and KC pancreas. Likewise, acinar-mCAF cocultures revealed induction of ductal transdifferentiation in cell-line, acinar-organoid, and explant coculture formats in WT and KC mice pancreas. Proteomic and transcriptomic data integration revealed a novel Laminin5/Integrinα4/Stat3 axis responsible for CAF-mediated acinar to ductal cell transdifferentiation. Results collectively suggest the first evidence for CAF-influenced acino-ductal phenotypic switchover, thus highlighting the role of the tumor micro-environment in the inception of pancreatic carcinogenesis.
2025-01-08 | GSE249567 | GEO
Project description:Transdifferentiation and changes of cellular identity are hallmarks of malignant transformation1-3. As such, the process of acinar-to-ductal metaplasia (ADM) represents a fundamental step in pancreatic ductal adenocarcinoma (PDAC) development, but regulatory pathways controlling ADM are not fully understood4,5. Here, we show that murine pancreatic acinar cells upregulate expression of CASPASE3, CASPASE8, RIPK3 and MLKL - key molecules driving both apoptosis and necroptosis6,7 - during transdifferentiation towards a duct-like phenotype. Spontaneous activation of these respective programmed cell death (PCD) pathways during KRAS-driven transdifferentiation is counterbalanced by transforming growth factor (TGF)-β-activated kinase 1 (TAK1), a kinase transmitting inhibitory phosphorylation signals towards the apoptosis- and necroptosis activator RIPK18. Genetic deletion or pharmacological inhibition of TAK1 simultaneously triggered apoptosis and necroptosis and thereby prevented KRAS-driven ADM in vitro as well as KRAS-driven PDAC in vivo. In line, TAK1 expression is upregulated in human PDAC cells, and pharmacological inhibition of TAK1 triggered PCD in organoid and spheroid cells derived from PDAC patients. Collectively, these findings suggest that TAK1 defines a decision point between ADM and PCD in pancreas cells and represents a promising pharmacological target for the prevention and treatment of PDAC patients.
2024-11-29 | GSE223135 | GEO
Project description:This experiment used RNA-Seq technology to explore gene expression in mouse FACS-purified pancreatic P60 Acinar cells, P60 Beta-cells, 1 day 3TF (MafA/Neurog3/Pdx1)-induced Acinar cells and 7 days 3TF-induced Acinar cells.ďż˝
2016-07-06 | E-MTAB-3921 | biostudies-arrayexpress
Project description:Type 1 diabetes is characterized by the destruction of pancreatic beta cells, and generating new insulin-producing cells from other cell types is a major aim of regenerative medicine. One promising approach is transdifferentiation of developmentally related pancreatic cell types including glucagon-producing alpha cells. In a genetic model, overexpression of the master regulatory transcription factor Pax4 or loss of its counterplayer Arx are sufficient to induce the conversion of alpha cells to functional beta-like cells. Here we identify artemisinins as small molecules that functionally repress Arx and induce beta-cell characteristics in alpha cells. We show that the protein gephyrin is the mammalian target of these antimalaria drugs. Finally, we demonstrate that gephyrin-mediated enhancement of GABAA receptor signaling is the mechanism of action of these molecules in pancreatic transdifferentiation. Our results indicate that gephyrin is a novel druggable target for the regeneration of pancreatic beta cell mass from alpha cells.
2017-01-19 | GSE84714 | GEO
Project description:Insufficient functional β-cell mass causes diabetes; however, an effective cell replacement therapy for curing diabetes is currently not available. Reprogramming of acinar cells toward functional insulin-producing cells would offer an abundant and autologous source of insulin-producing cells. Our lineage tracing studies along with transcriptomic characterization demonstrate that treatment of adult mice with a small molecule that specifically inhibits kinase activity of focal adhesion kinase results in trans-differentiation of acinar cells into insulin producing β-like cells. The acinar-derived insulin-producing cells infiltrate the pre-existing endocrine islets, partially restore β-cell mass, and significantly improve glucose homeostasis in diabetic mice. Importantly, this treatment can substantially reduce the exogenous insulin requirements in streptozotocin-induced diabetic non-human primates. These findings provide evidence that inhibition of the kinase activity of focal adhesion kinase can convert acinar cells into insulin-producing cells and could offer a promising strategy for treating diabetes.
2024-03-12 | GSE251852 | GEO
Project description:Multipotent pancreatic progenitors (MPC) are defined as Ptf1a+, Mychigh, Cpa+ cells. During the transition from MPC to unipotent acinar progenitors, c-Myc is down-regulated whereas Ptf1a is up-regulated, leading to the deployment of the acinar program. Here, we show that c-Myc and Ptf1a interact directly and c-Myc binds to, and represses, the transcriptional activity of the PTF1 complex in vitro and in vivo. Using Ela1-Myc mice, in which c-Myc is overexpressed in acinar cells starting at E14.5, we find that acinar cells fail to undergo normal maturation at P1 and this is followed by a massive subsequent repression of the acinar programme. Lineage tracing with Ptf1aCreERT2;Rosa26YFP and Ela1-Myc;Ptf1aCreERT2;Rosa26YFP mice receiving TMX at E15.5 and analyzed at E18.5 revealed that c-Myc overexpression is associated with activation of a hepatic programme but not with pancreatic lineage misspecification At 8 weeks, the silencing of the acinar program is associated with increased expression of the PRC2 complex in a c-Myc dependent manner. Genome wide studies show that Ptf1a and c-Myc display partially overlapping chromatin occupancy patterns and DNA binding competition. We conclude that c-Myc down-regulation during development is crucial for the maturation of pre-acinar to acinar cells. c-Myc overexpression may contribute to pancreatic carcinogenesis by restraining cell differentiation and rendering cells susceptible to transformation.
2017-12-11 | GSE77410 | GEO
Project description:Multipotent pancreatic progenitors (MPC) are defined as Ptf1a+, Mychigh, Cpa+ cells. During the transition from MPC to unipotent acinar progenitors, c-Myc is down-regulated whereas Ptf1a is up-regulated, leading to the deployment of the acinar program. Here, we show that c-Myc and Ptf1a interact directly and c-Myc binds to, and represses, the transcriptional activity of the PTF1 complex in vitro and in vivo. Using Ela1-Myc mice, in which c-Myc is overexpressed in acinar cells starting at E14.5, we find that acinar cells fail to undergo normal maturation at P1 and this is followed by a massive subsequent repression of the acinar programme. Lineage tracing with Ptf1aCreERT2;Rosa26YFP and Ela1-Myc;Ptf1aCreERT2;Rosa26YFP mice receiving TMX at E15.5 and analyzed at E18.5 revealed that c-Myc overexpression is associated with activation of a hepatic programme but not with pancreatic lineage misspecification At 8 weeks, the silencing of the acinar program is associated with increased expression of the PRC2 complex in a c-Myc dependent manner. Genome wide studies show that Ptf1a and c-Myc display partially overlapping chromatin occupancy patterns and DNA binding competition. We conclude that c-Myc down-regulation during development is crucial for the maturation of pre-acinar to acinar cells. c-Myc overexpression may contribute to pancreatic carcinogenesis by restraining cell differentiation and rendering cells susceptible to transformation.
2017-12-11 | GSE77409 | GEO
Project description:Heart failure is a syndrome with a pathophysiological basis that can be traced to dysfunction in several interconnected molecular pathways. Identification of biomarkers of heart failure that allow measurement of the disease on a molecular level has resulted in enthusiasm for their use in prognostication and selection of appropriate therapies. However, despite considerable amounts of information available on numerous biomarkers, inconsistent research methodologies and lack of clinical correlations have made bench-to-bedside translations rare and left the literature with countless publications of varied quality. There is a need for a systematic and collaborative approach aimed at definitively studying the clinical benefits of novel biomarkers. In this review, on the basis of input from academia, industry, and governmental agencies, we propose a systematized approach based on adherence to specific quality measures for studies looking to augment current prediction model or use biomarkers to tailor therapeutics. We suggest that study quality, rather than results, should determine publication and propose a system for grading biomarker studies. We outline the need for collaboration between clinical investigators and statisticians to introduce more advanced statistical methodologies into the field of biomarkers that would allow for data from a large number of variables to be distilled into clinically actionable information. Lastly, we propose the creation of a heart failure biomarker consortium that would allow for a comprehensive list of biomarkers to be concomitantly analyzed in a pooled sample of randomized clinical trials and hypotheses to be generated for testing in biomarker-guided trials. Such a consortium could collaborate in sharing samples to identify biomarkers, undertake meta-analyses on completed trials, and spearhead clinical trials to test the clinical utility of new biomarkers.
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Project description:Cancer-associated Fibroblast Induces Acinar-to-ductal Cell Transdifferentiation and Pancreatic Cancer Initiation via LAMA5/ITGA4 axis
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