Pancreatic islet cell type–specific transcriptomic changes during pregnancy and postpartum

Chung, Jin Yong; Ma, Yuanyuan; Zhang, Dingguo; Bickerton, Hayden; Stokes, Eric; Patel, Sweta B.; Tse, Hubert M.; Feduska, Joseph M.; Welner, Rob S.; Banerjee, Ronadip R.

doi:10.1016/j.isci.2023.106439

Cited by 4 publications

(5 citation statements)

References 67 publications

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“…In our dataset, in T2D islets, we find that PLCE1 expression increases in α1 and α2 (mature α-cells) and decreases further from the already very low expression level in mature β1 cells confirming previous results and highlighting this phospholipase as a potential candidate for β-cell dysfunction in T2D. Pappalysin-2 (PAPPA2), an enzyme that cleaves and inactivates IGFBP proteins, is upregulated in α-cells during gestation (50). In our study, we observe that PAPPA2 is expressed in α-cells and may participate in the transition of AB/β-cells into α-cells by suppressing the effects of IGFBPs since IGFBP1 has been reported to promote α- to β-cell transdifferentiation (51).…”

Section: Discussionsupporting

confidence: 89%

Human Pancreatic α-Cell Heterogeneity and Trajectory Inference Analysis Using Integrated Single Cell- and Single Nucleus-RNA Sequencing Platforms

Kang,

Lee,

Varela

et al. 2023

Preprint

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Prior studies have shown that pancreatic α-cells can transdifferentiate into β-cells, and that β-cells de-differentiate and are prone to acquire an α-cell phenotype in type 2 diabetes (T2D). However, the specific human α-cell and β-cell subtypes that are involved in α-to-β-cell and β-to-α-cell transitions are unknown. Here, we have integrated single cell RNA sequencing (scRNA-seq) and single nucleus RNA-seq (snRNA-seq) of isolated human islets and human islet grafts and provide additional insight into α-β cell fate switching. Using this approach, we make seven novel observations. 1) There are five differentGCG-expressing human α-cell subclusters [α1, α2, α-β-transition 1 (AB-Tr1), α-β-transition 2 (AB-Tr2), and α-β (AB) cluster] with different transcriptome profiles in human islets from non-diabetic donors. 2) The AB subcluster displays multihormonal gene expression, inferred mostly from snRNA-seq data suggesting identification by pre-mRNA expression. 3) The α1, α2, AB-Tr1, and AB-Tr2 subclusters are enriched in genes specific for α-cell function while AB cells are enriched in genes related to pancreatic progenitor and β-cell pathways; 4) Trajectory inference analysis of extracted α- and β-cell clusters and RNA velocity/PAGA analysis suggests a bifurcate transition potential for AB towards both α- and β-cells. 5) Gene commonality analysis identifiesZNF385D, TRPM3, CASR, MEG3andHDAC9as signature for trajectories moving towards β-cells andSMOC1, PLCE1, PAPPA2, ZNF331, ALDH1A1, SLC30A8, BTG2, TM4SF4, NR4A1andPSCK2as signature for trajectories moving towards α-cells. 6) Remarkably, in contrast to the eventsin vitro, the AB subcluster is not identifiedin vivoin human islet grafts and trajectory inference analysis suggests only unidirectional transition from α-to-β-cellsin vivo. 7) Analysis of scRNA-seq datasets from adult human T2D donor islets reveals a clear unidirectional transition from β-to-α-cells compatible with dedifferentiation or conversion into α-cells. Collectively, these studies show that snRNA-seq and scRNA-seq can be leveraged to identify transitions in the transcriptional status among human islet endocrine cell subpopulationsin vitro,in vivo, in non-diabetes and in T2D. They reveal the potential gene signatures for common trajectories involved in interconversion between α- and β-cells and highlight the utility and power of studying single nuclear transcriptomes of human isletsin vivo. Most importantly, they illustrate the importance of studying human islets in their naturalin vivosetting.

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Section: Discussionsupporting

confidence: 89%

Human Pancreatic α-Cell Heterogeneity and Trajectory Inference Analysis Using Integrated Single Cell- and Single Nucleus-RNA Sequencing Platforms

Kang,

Lee,

Varela

et al. 2023

Preprint

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“…Similar to the bulk RNAseq data, ( 21–23 )among the subpopulations identified in the integrated atlas, the capillary 1 subpopulation had the highest enrichment for the module score for the pancreas EC enriched signature (Fig 6E), followed by the arteriole population. This suggests that it is the capillary 1 subpopulation that is driving this signature in pancreatic ECs and that the arteriole population is also specialized.…”

Section: Resultssupporting

confidence: 69%

“…This further supports that capillary 1 is the more specialized endocrine/islet-specific capillary population, while capillary 2 is the more generic exocrine capillary population. Recent publications (21)(22)(23) have also conducted scRNAseq of isolated islet cells and have uncovered markers for the endothelial population, which should majorly constitute the islet capillary ECs as well the feeding arteriole ECs. We've assessed these markers in the integrated map and demonstrated that capillary 1 highly expressed all these islet endothelial markers except IGFBP3, which as we demonstrated, is enriched in the arteriole population (Fig.…”

Section: Validation Of An Islet-specific Ec Cell Population and Signa...mentioning

confidence: 99%

“…When the whole pancreas is dissociated into single cells/nuclei, these enzymes interfere with sequencing data. As a result, the majority of the pancreas datasets have sequenced isolated, in vitro cultured islets (14)(15)(16)(17)(18)(19)(20)(21)(22)(23), which have low number of ECs sequenced. Therefore, these datasets do not allow for dissecting intra tissue pancreatic endothelial heterogeneity (exocrine vs endocrine).…”

Section: Introductionmentioning

confidence: 99%

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Uncovering the heterogeneity of pancreatic endothelial cells using integrative and comparative single cell gene expression analysis

Khan

Ahuja

Taïb

et al. 2023

Preprint

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The pancreatic islet vasculature displays tissue-specific physiological and functional adaptations that support rapid glucose sensing and insulin response by beta-cells. To uncover the transcriptomic basis of this specialization, we performed a meta-analysis of multi-organ single cell RNA sequencing atlases employing a unique strategy to avoid transcriptomic contamination. We identified biologically relevant genes involved in sphingosine-1-phosphate-mediated insulin secretion (PLPP1, RDX, CDC42), islet basement membrane formation (SPARC, COL15A1), endothelial cell (EC) permeability (PLVAP, EHD4), membrane transporters (CD320, SLCO2A1) and developmental transcription factors (NKX2-3, AHR). These were validated in silico in an independent dataset. We further established the first integrated transcriptomic atlas of human pancreatic ECs and described two unique capillary subpopulations: exocrine and endocrine pancreas ECs. We validated the spatial localization of key markers using RNAscope and immunofluorescence staining on mouse pancreatic tissue cross-sections. Our findings provide novel insights into pancreatic EC heterogeneity and islet EC function with potential implications in therapeutic strategies.

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“…The proportional presence of delta-cells did not change during mouse pregnancy, suggesting that delta-cell mass must increase in absolute terms across gestation relative to the increase in beta-cell mass, and the proportion of delta cells increased still further in a diabetes model [276]. Following pregnancy, both beta-and alpha-cell mass return to pre-pregnancy levels through targeted apoptosis in rodents [266,277], and presumably in humans as well.…”

Section: Pregnancy and Gestational Diabetesmentioning

confidence: 94%

The Importance of Intra-Islet Communication in the Function and Plasticity of the Islets of Langerhans during Health and Diabetes

Hill,

Hill

2024

IJMS

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Islets of Langerhans are anatomically dispersed within the pancreas and exhibit regulatory coordination between islets in response to nutritional and inflammatory stimuli. However, within individual islets, there is also multi-faceted coordination of function between individual beta-cells, and between beta-cells and other endocrine and vascular cell types. This is mediated partly through circulatory feedback of the major secreted hormones, insulin and glucagon, but also by autocrine and paracrine actions within the islet by a range of other secreted products, including somatostatin, urocortin 3, serotonin, glucagon-like peptide-1, acetylcholine, and ghrelin. Their availability can be modulated within the islet by pericyte-mediated regulation of microvascular blood flow. Within the islet, both endocrine progenitor cells and the ability of endocrine cells to trans-differentiate between phenotypes can alter endocrine cell mass to adapt to changed metabolic circumstances, regulated by the within-islet trophic environment. Optimal islet function is precariously balanced due to the high metabolic rate required by beta-cells to synthesize and secrete insulin, and they are susceptible to oxidative and endoplasmic reticular stress in the face of high metabolic demand. Resulting changes in paracrine dynamics within the islets can contribute to the emergence of Types 1, 2 and gestational diabetes.

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Pancreatic islet cell type–specific transcriptomic changes during pregnancy and postpartum

Cited by 4 publications

References 67 publications

Human Pancreatic α-Cell Heterogeneity and Trajectory Inference Analysis Using Integrated Single Cell- and Single Nucleus-RNA Sequencing Platforms

Human Pancreatic α-Cell Heterogeneity and Trajectory Inference Analysis Using Integrated Single Cell- and Single Nucleus-RNA Sequencing Platforms

Uncovering the heterogeneity of pancreatic endothelial cells using integrative and comparative single cell gene expression analysis

The Importance of Intra-Islet Communication in the Function and Plasticity of the Islets of Langerhans during Health and Diabetes

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