RNA sequencing of pancreatic islets and islet-derived macrophages and endothelial cells modulated by vascular endothelial growth factor-A signaling
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE72546 | GEO | 2015/09/01
SECONDARY ACCESSION(S): PRJNA294308
REPOSITORIES: GEO
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Project description:Pancreatic islet endocrine cell and endothelial cell (EC) interactions mediated by vascular endothelial growth factor-A (VEGF-A) signaling are important for islet endocrine cell differentiation and the formation of highly vascularized islets. To dissect how VEGF-A signaling modulates intra-islet vasculature and innervation, islet microenvironment, and beta cell mass, we transiently increased VEGF-A production by beta cells. VEGF-A induction dramatically increased the number of intra-islet ECs but led to beta cell loss. After withdrawal of the VEGF-A stimulus, beta cell mass, function, and islet structure normalized as a result of a robust, but transient, burst in proliferation of pre-existing beta cells. Bone marrow-derived macrophages recruited to the site of beta cell injury were crucial for the beta cell proliferation, which was independent of pancreatic location and circulating factors such as glucose. Identification of the signals responsible for the proliferation of adult, terminally differentiated beta cells will improve strategies aimed at beta cell regeneration and expansion.
2021-03-23 | GSE163825 | GEO
Project description:Pancreatic islet endocrine cell and endothelial cell (EC) interactions mediated by vascular endothelial growth factor-A (VEGF-A) signaling are important for islet endocrine cell differentiation and the formation of highly vascularized islets. To dissect how VEGF-A signaling modulates intra-islet vasculature and innervation, islet microenvironment, and β cell mass, we transiently increased VEGF-A production by β cells. VEGF-A induction dramatically increased the number of intra-islet ECs but led to β cell loss. After withdrawal of the VEGF-A stimulus, β cell mass, function, and islet structure normalized as a result of a robust, but transient, burst in proliferation of pre-existing β cells. Bone marrow-derived macrophages (MΦs) recruited to the site of β cell injury were crucial for the β cell proliferation, which was independent of pancreatic location and circulating factors such as glucose. Identification of the signals responsible for the proliferation of adult, terminally differentiated β cells will improve strategies aimed at β cell regeneration and expansion. Examination of RNA profiles from isolated whole islets from RIP-rtTA; TetO-VEGF-A mice with no doxycycline (Dox) treatment (3 samples) and after 1 week of Dox (3 sample); and islet-derived macrophages (3 samples) and endothelial cells (3 samples) isolated from dispersed purified islets from RIP-rtTA; TetO-VEGF-A mice after 1 week Dox treatment by fluorescence-activated cell sorting using antibodies against CD11b and CD31, respectively.
2015-09-01 | E-GEOD-72546 | biostudies-arrayexpress
Project description:The inability of the beta-cell to meet the demand for insulin brought about by insulin resistance leads to type 2 diabetes. In adults, beta-cell replication is one of the mechanisms thought to cause the expansion of beta-cell mass. Efforts to treat diabetes require knowledge of the pathways that drive facultative beta-cell proliferation in vivo. A robust physiological stimulus of beta-cell expansion is pregnancy, and identifying the mechanisms underlying this stimulus may provide therapeutic leads for the treatment of type 2 diabetes. The peak in beta-cell proliferation during pregnancy occurs on day 14.5 of gestation in mice. Using advanced genomic approaches, we globally characterize the gene expression signature of pancreatic islets on day 14.5 of gestation during pregnancy. We identify a total of 1,907 genes as differentially expressed in the islet during pregnancy. We demonstrate that the islet's ability to compensate for relative insulin deficiency during metabolic stress is associated with the induction of both proliferative and survival pathways. A comparison of the genes induced in three different models of islet expansion suggests that diverse mechanisms can be recruited to expand islet mass. The identification of many novel genes involved in islet expansion during pregnancy provides an important resource for diabetes researchers to further investigate how these factors contribute to the maintenance of not only islet mass, but ultimately beta-cell mass.
2010-06-26 | E-MTAB-120 | biostudies-arrayexpress
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.
2021-10-22 | GSE159970 | GEO
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.
2021-10-22 | GSE159844 | GEO
Project description:β cell proliferation rates decline with age and adult β cells have limited self-duplicating activity for regeneration, which predisposes to diabetes. Here we show that, among MYC family members, Mycl was expressed preferentially in proliferating immature endocrine cells. Genetic ablation of Mycl caused a modest reduction in cell proliferation of pancreatic endocrine cells in neonatal mice. By contrast, systemic expression of Mycl in mice stimulated proliferation in pancreatic islet cells and resulted in expansion of pancreatic islets without forming tumors in other organs. Single-cell RNA sequencing and genetic tracing experiments revealed that the expression of Mycl provoked transcription signatures associated with immature proliferating endocrine cells and stimulated self-duplication in adult hormone-expressing cells. The expanded hormone-expressing cells ceased proliferation but persisted after withdrawal of Mycl expression. Remarkably, a subset of the expanded α cells gave rise to insulin-producing cells after the withdrawal. Moreover, transient Mycl expression in vivo was sufficient to normalize increased blood glucose levels in diabetic mice evoked by chemical ablation of β cells. In vitro expression of Mycl similarly provoked active replication without inducing apoptosis in adult hormone-expressing islet cells, even those from aged mice. Furthermore, the expanded islet cells functioned in diabetic mice after transplantation. Finally, we show that MYCL stimulated self-duplication of human adult cadaveric islet cells. Collectively, these results demonstrate that sole induction of Mycl expands adult β cells both in vivo and in vitro. Moreover, islet cell-specific reprogramming via transient Mycl transduction elicits endogenous expansion of insulin-producing cells in adult pancreas through both self-duplication of β cells and transdifferentiation ofα cells into insulin-producing cells, which may provide a regenerative strategy of β cells.
2022-01-29 | GSE163947 | GEO
Project description:β cell proliferation rates decline with age and adult β cells have limited self-duplicating activity for regeneration, which predisposes to diabetes. Here we show that, among MYC family members, Mycl was expressed preferentially in proliferating immature endocrine cells. Genetic ablation of Mycl caused a modest reduction in cell proliferation of pancreatic endocrine cells in neonatal mice. By contrast, systemic expression of Mycl in mice stimulated proliferation in pancreatic islet cells and resulted in expansion of pancreatic islets without forming tumors in other organs. Single-cell RNA sequencing and genetic tracing experiments revealed that the expression of Mycl provoked transcription signatures associated with immature proliferating endocrine cells and stimulated self-duplication in adult hormone-expressing cells. The expanded hormone-expressing cells ceased proliferation but persisted after withdrawal of Mycl expression. Remarkably, a subset of the expanded α cells gave rise to insulin-producing cells after the withdrawal. Moreover, transient Mycl expression in vivo was sufficient to normalize increased blood glucose levels in diabetic mice evoked by chemical ablation of β cells. In vitro expression of Mycl similarly provoked active replication without inducing apoptosis in adult hormone-expressing islet cells, even those from aged mice. Furthermore, the expanded islet cells functioned in diabetic mice after transplantation. Finally, we show that MYCL stimulated self-duplication of human adult cadaveric islet cells. Collectively, these results demonstrate that sole induction of Mycl expands adult β cells both in vivo and in vitro. Moreover, islet cell-specific reprogramming via transient Mycl transduction elicits endogenous expansion of insulin-producing cells in adult pancreas through both self-duplication of β cells and transdifferentiation ofα cells into insulin-producing cells, which may provide a regenerative strategy of β cells.
2022-01-29 | GSE178726 | GEO
Project description:Diabetes mellitus results from an inadequately functioning beta-cell mass. In the adult pancreas, beta-cell mass is dynamic, increasing to meet metabolic demands and decreasing with metabolic or injury insults. Exendin-4 (Ex-4) is a glucagon-like peptide-1 receptor agonist that augments beta-cell mass by increasing beta-cell neogenesis and proliferation and by reducing apoptosis. We utilized a cDNA microarray approach to identify genes that are differentially regulated during islet growth after Ex-4 treatment or a partial pancreatectomy (Ppx). Mice underwent 50% Ppx or sham operation and received Ex-4 or vehicle every 24 hours. cDNA prepared from total pancreatic RNA isolated at 12, 24 and 48 hrs after surgery was hybridized to the PancChip 4.0 microarray.
2005-12-01 | E-CBIL-5 | biostudies-arrayexpress
Project description:Inflammation is a key component of the pathogenesis of obesity-associated type 2 diabetes (T2D). However, the nature of T2D-associated islet inflammation and its impacts on T2D-associated beta cell abnormalities remain poorly defined. Using both diet-induced and genetically modified T2D animal models, we explore immune components of islet inflammation and define their roles in regulating beta cell function and proliferation. Our studies show that T2D-associated islet inflammation is uniquely dominated by macrophages, without the involvement of adaptive immune cells. We identify two islet macrophage populations, characterized by their distinct phenotypes, anatomical distributions and functional properties. Obesity induces a local expansion of intra-islet macrophages, independent of the replenishment from circulating monocytes. In contrast, the abundance of peri-islet macrophages is negligibly affected by obesity. Functionally, intra-islet macrophages impair beta cell function in a cell-cell contact dependent manner. In contrast, both intra- and peri-islet macrophage populations are able to promote beta cell proliferation. Together, these data provide a definitive view of the genesis of T2D-associated islet inflammation and define specific roles of islet macrophages in regulating beta cell function and proliferation.
2019-01-02 | GSE112002 | GEO
Project description:Direct lineage conversion of adult cells is a promising approach for regenerative medicine. A major challenge of lineage conversion is to generate specific subtypes of cells, closely related cells with distinct properties. The pancreatic islets contain three major hormone-secreting endocrine subtypes: insulin+ β-cells, glucagon+ α-cells, and somatostatin+ δ-cells. We previously reported that a combination of three transcription factors, Ngn3, Mafa, and Pdx1, directly reprogram pancreatic acinar cells to β-cells. We now show that acinar cells can be converted to δ-like and α-like cells by Ngn3 and Ngn3+Mafa respectively. Thus, three major islet endocrine subtypes can be derived by acinar reprogramming. Ngn3 promotes establishment of a generic endocrine state in acinar cells at the onset of reprogramming in addition to promoting δ-specification. Mafa and Pdx1 suppress δ-specification in α- and β-cell formation. These studies identify a set of defined factors whose combinatorial actions reprogram acinar cells to distinct islet endocrine subtypes in vivo. induced beta cells samples at day 10 collected for the microarray
2013-11-20 | E-GEOD-52522 | biostudies-arrayexpress