Islet single-cell transcriptomic profiling during obesity-induced beta cell expansion
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ABSTRACT:
PROVIDER: PRJNA1090114 | ENA |
REPOSITORIES: ENA
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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.
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Project description:We found that in rodents, b-cell mass expansion during pregnancy and obesity is associated with changes in the expression of a group of islet microRNAs. We were able to reproduce in isolated pancreatic islets the decrease of miR-338-3p level observed in gestation and obesity by activating the G-protein coupled estrogen receptor GPR30 and the GLP1 receptor. Blockade of miR-338-3p in b-cells using specific anti-miR molecules mimicked gene expression changes occurring during b-cell mass expansion and resulted in increased proliferation and improved survival both in vitro and in vivo. These findings point to a major role for miR-338-3p in compensatory b-cell mass expansion occurring under different insulin resistance states.
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Project description:Type 2 diabetes (T2D) is associated with compromised identity of insulin-producing pancreatic islet beta (β) cells, characterized by inappropriate production of other islet cell-enriched hormones. Here we examined how hormone misexpression was influenced by the MAFA and MAFB transcription factors, closely related proteins that maintain islet cell function. Mice specifically lacking MafA in β cells demonstrated broad, population-wide changes in hormone gene expression with an overall gene signature closely resembling islet gastrin (Gast)-positive cells generated under conditions of chronic hyperglycemia and obesity. A human b cell line deficient in MAFB, but not one lacking MAFA, also produced a gastrin (GAST)-positive gene expression pattern. In addition, GAST was detected in human T2D β cells with low levels of MAFB. Moreover, evidence is provided that human MAFB can directly repress GAST gene transcription. These results support a novel, species-specific role for MafA and MAFB in maintaining adult mouse and human β cell identity, respectively, by repressing expression of Gast/GAST and other non-b cell hormones.
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Project description:We found that in rodents, postnatal beta-cell maturation is associated with changes in the expression of several islet microRNAs and discovered that these modifications are driven by changes in the nutrient supply. Mimicking the microRNA changes observed during β-cell maturation in newborn rat islet cells was sufficient to promote glucose-induced insulin release and to achieve a mature β-cell secretory phenotype. Moreover, the modifications in the level of some of these microRNAs reduced the proliferation of newborn β-cells, suggesting that they contribute to the limited proliferative capacity of adult β-cells. These findings demonstrated that miRNAs contribute to postnatal beta-cell maturation and development. Their role is likely to promote beta-cell adaptation to fule supply and to maintain glucose homeostasis by regulating insulin release and proliferation. Islets from 10-day-old rats (P10) (n=3) or 3-month-old male rat (n=3) were taken. Total RNA was extracted and mRNA profiling via Illumina single-end sequencing of mRNA-seq libraries was performed.
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Project description:Blood vessels play a critical role in pancreatic islet health and function, yet current culture methods to generate islet organoids from human pluripotent stem cells (SC-islets) lack a vascular component. Here, we engineered 3D vascularized SC-islet organoids by assembling SC-islet cells, human primary endothelial cells (ECs) and fibroblasts both in a non-perfused model and a microfluidic device with perfused vessels. Vasculature improved stimulus-dependent Ca2+ influx into SC-β-cells; a hallmark of β-cell function that is blunted in non-vascularized SC-islets. We show that an islet-like basement membrane is formed by vasculature and contributes to the functional improvement of SC-β-cells. Furthermore, cell-cell communication networks based on scRNA-seq data predicted BMP2/4-BMPR2 signaling from ECs to SC-β-cells. Correspondingly, BMP4 augmented the SC-β-cell Ca2+ response and insulin secretion. The here-described vascularized SC-islet models will enable further studies of crosstalk between β-cells and ECs and serve as an in vivo-mimicking platform for disease modeling and therapeutic testing.
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