Single-cell RNA-seq transcriptomic landscape of human and mouse islets and pathological alterations of diabetes

Chen, Kai; Zhang, Junqing; Huang, Yi; Tian, Xiaodong; Yang, Yinmo; Dong, Aimei

doi:10.1016/j.isci.2022.105366

Cited by 15 publications

(14 citation statements)

References 63 publications

(105 reference statements)

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“… 43 However, we did not observe any change in extracellular acetate in mouse islets between LG and HG, which we suggest is because of the low expression of MCTs in mouse islets. 44 , 45 Another limitation is that we did not explore acetate secretion at different glucose concentrations with human islets. Though conducting similar studies on human islets will be important, the results could be confounding due to the known functional heterogeneity of the human islets.…”

Section: Discussionmentioning

confidence: 99%

β cell acetate production and release are negligible

Xu,

Nnyamah,

Pandya

et al. 2024

Islets

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Background Studies suggest that short chain fatty acids (SCFAs), which are primarily produced from fermentation of fiber, regulate insulin secretion through free fatty acid receptors 2 and 3 (FFA2 and FFA3). As these are G-protein coupled receptors (GPCRs), they have potential therapeutic value as targets for treating type 2 diabetes (T2D). The exact mechanism by which these receptors regulate insulin secretion and other aspects of pancreatic β cell function is unclear. It has been reported that glucose-dependent release of acetate from pancreatic β cells negatively regulates glucose stimulated insulin secretion. While these data raise the possibility of acetate’s potential autocrine action on these receptors, these findings have not been independently confirmed, and multiple concerns exist with this observation, particularly the lack of specificity and precision of the acetate detection methodology used. Methods Using Min6 cells and mouse islets, we assessed acetate and pyruvate production and secretion in response to different glucose concentrations, via liquid chromatography mass spectrometry. Results Using Min6 cells and mouse islets, we showed that both intracellular pyruvate and acetate increased with high glucose conditions; however, intracellular acetate level increased only slightly and exclusively in Min6 cells but not in the islets. Further, extracellular acetate levels were not affected by the concentration of glucose in the incubation medium of either Min6 cells or islets. Conclusions Our findings do not substantiate the glucose-dependent release of acetate from pancreatic β cells, and therefore, invalidate the possibility of an autocrine inhibitory effect on glucose stimulated insulin secretion.

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Section: Discussionmentioning

confidence: 99%

β cell acetate production and release are negligible

Xu,

Nnyamah,

Pandya

et al. 2024

Islets

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“…Compositional scRNA-seq analyses are becoming more common to discern differences between disease trajectories (Ordovas-Montanes et al, 2018;Smillie et al, 2019;Zheng et al, 2021), treatment groups (Darrah et al, 2020;Zhang et al, 2022b), and/or species (Chen et al, 2022;Li et al, 2022). Current tools focus on identifying specific clusters or gene programs that are compositionally distinct between groups (Büttner et al, 2021;Cao et al, 2019;Dann et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

Primary nasal viral infection rewires the tissue-scale memory response

Kazer,

Match,

Langan

et al. 2023

Preprint

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The nasal mucosa is frequently the initial site of respiratory viral infection, replication, and transmission. Recent work has started to clarify the independent responses of epithelial, myeloid, and lymphoid cells to viral infection in the nasal mucosa, but their spatiotemporal coordination and relative importance remain unclear. Furthermore, understanding whether and how primary infection shapes tissue-scale memory responses to secondary challenge is critical for the rational design of nasal-targeting therapeutics and vaccines. Here, we generated a single-cell RNA-sequencing (scRNA-seq) atlas of the murine nasal mucosa sampling three distinct regions before and during primary and secondary influenza infection. Primary infection was largely restricted to respiratory mucosa and induced stepwise changes in cell type, subset, and state composition over time. Interferon (IFN)-responsive neutrophils appeared 2 days post infection (dpi) and preceded transient IFN-responsive/cycling epithelial cell responses 5 dpi, which coincided with broader antiviral monocyte and NK cell accumulation. By 8 dpi, monocyte-derived macrophages expressingCxcl9andCxcl16arose alongside effector cytotoxic CD8 andIfng-expressing CD4 T cells. Following viral clearance (14 dpi), rare, previously undescribedMeg3+MHC-II+ epithelial cells andKrt13+nasalimmune-interactingfloorepithelial (KNIIFE) cells expressing multiple genes with immune communication potential increased concurrently with tissue-resident memory T (TRM)-like cells and IgG+/IgA+ plasma cells. Proportionality analysis coupled with cell-cell communication inference underscored the CXCL16–CXCR6 signaling axis in effector CD8 T cell and TRMcell formation in the nasal mucosa. Secondary influenza challenge administered 60 dpi induced an accelerated and coordinated myeloid and lymphoid response with reduced IFN-responsive epithelial activity, illustrating how tissue-scale memory to natural infection engages both myeloid and lymphoid cells without broad epithelial inflammation. Together, this atlas serves as a reference for viral infection in the upper respiratory tract and highlights the efficacy of local coordinated memory responses upon rechallenge.

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“…Combining the published scRNA-seq dataset ( 21 ), we also attempt to score each cell using signatures of unperturbed endogenous adult acinar cells and β cells to evaluate the relative changes in cell transcriptome profiles during the transdifferentiation process, in which cells gradually lose acinar cell signatures and acquire β cell signatures (details see the Supplementary Text and fig. S5).…”

Section: Discussionmentioning

confidence: 99%

Charting a high-resolution roadmap for regeneration of pancreatic β cells by in vivo transdifferentiation from adult acinar cells

Liu

et al. 2023

Sci. Adv.

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Adult mammals have limited capacity to regenerate functional cells. Promisingly, in vivo transdifferentiation heralds the possibility of regeneration by lineage reprogramming from other fully differentiated cells. However, the process of regeneration by in vivo transdifferentiation in mammals is poorly understood. Using pancreatic β cell regeneration as a paradigm, we performed a single-cell transcriptomic study of in vivo transdifferentiation from adult mouse acinar cells to induced β cells. Using unsupervised clustering analysis and lineage trajectory construction, we uncovered that the cell fate remodeling trajectory was linear at the initial stage and the reprogrammed cells either evolved to induced β cells or toward a “dead-end” state after day 4.Moreover, functional analyses identified both p53 and Dnmt3a that acted as reprogramming barriers during the process of in vivo transdifferentiation. Collectively, we decipher a high-resolution roadmap of regeneration by in vivo transdifferentiation and provide a detailed molecular blueprint to facilitate mammalian regeneration.

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Single-cell RNA-seq transcriptomic landscape of human and mouse islets and pathological alterations of diabetes

Cited by 15 publications

References 63 publications

β cell acetate production and release are negligible

β cell acetate production and release are negligible

Primary nasal viral infection rewires the tissue-scale memory response

Charting a high-resolution roadmap for regeneration of pancreatic β cells by in vivo transdifferentiation from adult acinar cells

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