An integrated map of cell type-specific gene expression in pancreatic islets

Elgamal, Ruth; Kudtarkar, Parul; Melton, Rebecca; Mummey, Hannah M; Benaglio, Paola; Okino, Mei-Lin; Gaulton, Kyle J.

doi:10.1101/2023.02.03.526994

Cited by 18 publications

(43 citation statements)

References 48 publications

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“…As shown in Figure 1B , our qPCR analysis revealed that Il33 expression in pancreatic pericytes was two orders of magnitude higher than in other analyzed cell populations. Similarly, IL33 expression in the human islets was restricted to the pericytic cell cluster ( Figure S1 ) ( 48 ).…”

Section: Resultsmentioning

confidence: 92%

“…As shown in Figure 1A , mouse pancreatic pericytes express IL-33 but no other members of the IL-1 family of cytokines. To define IL33 expression in human islets, we employed a published islet cell transcriptome ( 48 ). Indeed, IL33 is expressed by pericytes, identified by the pericytic markers PDGFRB , ACTA2 , ENG , and CD248 ( 30 , 48 )( Figure S1 ).…”

Section: Resultsmentioning

confidence: 99%

“…To define IL33 expression in human islets, we employed a published islet cell transcriptome ( 48 ). Indeed, IL33 is expressed by pericytes, identified by the pericytic markers PDGFRB , ACTA2 , ENG , and CD248 ( 30 , 48 )( Figure S1 ).…”

Section: Resultsmentioning

confidence: 99%

“…Published mouse pancreatic pericytes RNA sequencing ( 34 ) was deposited in ArrayExpress ( https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-5325/ ). Published islet genomic data ( 48 ) was accessed in http://www.gaultonlab.org/pages/Islet_expression_HPAP.html .…”

Section: Methodsmentioning

confidence: 99%

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Pericytes modulate islet immune cells and insulin secretion through Interleukin-33 production in mice

et al. 2023

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IntroductionImmune cells were recently shown to support β-cells and insulin secretion. However, little is known about how islet immune cells are regulated to maintain glucose homeostasis. Administration of various cytokines, including Interleukin-33 (IL-33), was shown to influence β-cell function. However, the role of endogenous, locally produced IL-33 in pancreatic function remains unknown. Here, we show that IL-33, produced by pancreatic pericytes, is required for glucose homeostasis.MethodsTo characterize pancreatic IL-33 production, we employed gene expression, flow cytometry, and immunofluorescence analyses. To define the role of this cytokine, we employed transgenic mouse systems to delete the Il33 gene selectively in pancreatic pericytes, in combination with the administration of recombinant IL-33. Glucose response was measured in vivo and in vitro, and morphometric and molecular analyses were used to measure β-cell mass and gene expression. Immune cells were analyzed by flow cytometry.ResutsOur results show that pericytes are the primary source of IL-33 in the pancreas. Mice lacking pericytic IL-33 were glucose intolerant due to impaired insulin secretion. Selective loss of pericytic IL-33 was further associated with reduced T and dendritic cell numbers in the islets and lower retinoic acid production by islet macrophages.DiscussionOur study demonstrates the importance of local, pericytic IL-33 production for glucose regulation. Additionally, it proposes that pericytes regulate islet immune cells to support β-cell function in an IL-33-dependent manner. Our study reveals an intricate cellular network within the islet niche.

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Section: Resultsmentioning

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Pericytes modulate islet immune cells and insulin secretion through Interleukin-33 production in mice

et al. 2023

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“…Gene expression signature scores were calculated using AddModuleScore function from Seurat package. To further confirm our cell annotations, first, we performed reference-based mapping using Azimuth R packages (version 0.4.6) 29 and employed previously annotated human islet cell dataset as reference 31 . Predicted cell annotation was projected on our integrated data UMAP with all cells, and the expression level of annotation markers used by Elgamal et al was visualized by DotPlot 31 .…”

Section: Methodsmentioning

confidence: 99%

Single Cell RNA-Seq Analysis of Regenerative Drug-Treated Human Pancreatic Islets Identifies A Cycling Alpha Cell Population As Key Beta Cell Progenitors

Karakose,

Wang,

Wang

et al. 2023

Preprint

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Diabetes ultimately results from an inadequate number of functional, insulin-producing human beta cells. Although current attempts to replenish the remaining beta cell pool in people with diabetes are encouraging, scalability and cost limit access for the millions of people with diabetes. The small molecule DYRK1A inhibitor class of beta cell regenerative drugs, either alone or in combination with GLP1 receptor agonists or TGF beta superfamily inhibitors, are capable of inducing beta cell replication in vitro and increasing beta cell mass in vivo. Despite these advances, the precise mechanisms of action of DYRK1A inhibitors remain incompletely understood. To address the mechanisms more deeply, we performed single cell RNA sequencing on human pancreatic islets treated with a DYRK1A inhibitor, either alone, or in combination with a GLP1 receptor agonist or a TGF beta superfamily inhibitor. We identify a cluster of Cycling Alpha Cells as the cells most responsive to DYRK1A inhibition. Velocity and pseudotime lineage trajectory analyses suggest that Cycling Alpha Cells serve as the primary target cell type for of DYRK1A inhibitors, and may serve as precursor cells that transdifferentiate into functional human beta cells in response to the DYRK1A inhibition. In addition to providing a novel mechanism of action for DYRK1A inhibitors, our findings suggest that efforts to target regenerative drugs to human beta cells may be mis-directed: the proper target may be Cycling Alpha Cells.

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Variant-to-function analysis of the childhood obesity chr12q13 locus implicates rs7132908 as a causal variant within the 3’ UTR ofFAIM2

Littleton,

Trang,

Volpe

et al. 2023

Preprint

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SUMMARYThe ch12q13 obesity locus is among the most significant childhood obesity loci identified in genome-wide association studies. This locus resides in a non-coding region withinFAIM2; thus, the underlying causal variant(s) presumably influence disease susceptibility via an influence oncis-regulation within the genomic region. We implicated rs7132908 as a putative causal variant at this locus leveraging a combination of our inhouse 3D genomic data, public domain datasets, and several computational approaches. Using a luciferase reporter assay in human primary astrocytes, we observed allele-specificcis-regulatory activity of the immediate region harboring rs7132908. Motivated by this finding, we went on to generate isogenic human embryonic stem cell lines homozygous for either rs7132908 allele with CRISPR-Cas9 homology-directed repair to assess changes in gene expression due to genotype and chromatin accessibility throughout a differentiation to hypothalamic neurons, a key cell type known to regulate feeding behavior. We observed that the rs7132908 obesity risk allele influenced the expression ofFAIM2along with other genes, decreased the proportion of neurons produced during differentiation, up-regulated cell death gene sets, and conversely down-regulated neuron differentiation gene sets. We have therefore functionally validated rs7132908 as a causal obesity variant which temporally regulates nearby effector genes at the ch12q13 locus and influences neurodevelopment and survival.

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An integrated map of cell type-specific gene expression in pancreatic islets

Cited by 18 publications

References 48 publications

Pericytes modulate islet immune cells and insulin secretion through Interleukin-33 production in mice

Pericytes modulate islet immune cells and insulin secretion through Interleukin-33 production in mice

Single Cell RNA-Seq Analysis of Regenerative Drug-Treated Human Pancreatic Islets Identifies A Cycling Alpha Cell Population As Key Beta Cell Progenitors

Variant-to-function analysis of the childhood obesity chr12q13 locus implicates rs7132908 as a causal variant within the 3’ UTR ofFAIM2

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