Maturation of beta cells: lessons from in vivo and in vitro models

Barsby, Tom; Otonkoski, Timo

doi:10.1007/s00125-022-05672-y

Cited by 29 publications

(25 citation statements)

References 151 publications

(213 reference statements)

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“…Our study is unique in that we found that most of the metabolic and exocytosis pathways related to beta cell maturation [ 40 ] were upregulated in CD81 low beta cells, with some difference in DEPs (such as PDX1 [ 41 ]), through single-cell proteomics, findings which are not replicated in scRNA-seq. Since the protein is the executor of biological function, these could suggest that CD81 low beta cells are functionally mature.…”

Section: Discussionmentioning

confidence: 95%

Single-cell RNA sequencing combined with single-cell proteomics identifies the metabolic adaptation of islet cell subpopulations to high-fat diet in mice

Jiang

et al. 2022

Diabetologia

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Aims/hypothesis Islets have complex heterogeneity and subpopulations. Cell surface markers representing alpha, beta and delta cell subpopulations are urgently needed for investigations to explore the compositional changes of each subpopulation in obesity progress and diabetes onset, and the adaptation mechanism of islet metabolism induced by a high-fat diet (HFD). Methods Single-cell RNA sequencing (scRNA-seq) was applied to identify alpha, beta and delta cell subpopulation markers in an HFD-induced mouse model of glucose intolerance. Flow cytometry and immunostaining were used to sort and assess the proportion of each subpopulation. Single-cell proteomics was performed on sorted cells, and the functional status of each alpha, beta and delta cell subpopulation in glucose intolerance was deeply elucidated based on protein expression. Results A total of 33,999 cells were analysed by scRNA-seq and clustered into eight populations, including alpha, beta and delta cells. For alpha cells, scRNA-seq revealed that the Ace2 low subpopulation had downregulated expression of genes related to alpha cell function and upregulated expression of genes associated with beta cell characteristics in comparison with the Ace2 high subpopulation. The impaired function and increased fragility of ACE2 low alpha cells exposure to HFD was further suggested by single-cell proteomics. As for beta cells, the CD81 high subpopulation may indicate an immature signature of beta cells compared with the CD81 low subpopulation, which had robust function. We also found differential expression of Slc2a2 in delta cells and a potentially stronger cellular function and metabolism in GLUT2 low delta cells than GLUT2 high delta cells. Moreover, an increased proportion of ACE2 low alpha cells and CD81 low beta cells, with a constant proportion of GLUT2 low delta cells, were observed in HFD-induced glucose intolerance. Conclusions/interpretation We identified ACE2, CD81 and GLUT2 as surface markers to distinguish, respectively, alpha, beta and delta cell subpopulations with heterogeneous maturation and function. The changes in the proportion and functional status of islet endocrine subpopulations reflect the metabolic adaptation of islets to high-fat stress, which weakened the function of alpha cells and enhanced the function of beta and delta cells to bring about glycaemic homeostasis. Our findings provide a fundamental resource for exploring the mechanisms maintaining each islet endocrine subpopulation’s fate and function in health and disease. Data availability The scRNA-seq analysis datasets from the cu...

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Section: Discussionmentioning

confidence: 95%

Single-cell RNA sequencing combined with single-cell proteomics identifies the metabolic adaptation of islet cell subpopulations to high-fat diet in mice

Jiang

et al. 2022

Diabetologia

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“…It is interesting to note that the expression of TGFB1 gene was also up-regulated in islets from 7-day-old compared to islets from 3-day-old pigs. TGFβ1 has been shown to play diverse roles in the development, proliferation, apoptosis, dedifferentiation, and function of islet beta cells in humans and rodents ( 37 – 39 ). For example, rat islets treated with TGFβ1 stimulates insulin secretion in low glucose condition but has no effect in high glucose condition ( 52 ).…”

Section: Discussionmentioning

confidence: 99%

Yield, cell composition, and function of islets isolated from different ages of neonatal pigs

Arefanian

Ramji²,

Gupta³

et al. 2022

Front. Endocrinol.

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The yield, cell composition, and function of islets isolated from various ages of neonatal pigs were characterized using in vitro and in vivo experimental models. Islets from 7- and 10-day-old pigs showed significantly better function both in vitro and in vivo compared to islets from 3- and 5-day-old pigs however, the islet yield from 10-day-old pigs were significantly less than those obtained from the other pigs. Since islets from 3-day-old pigs were used in our previous studies and islets from 7-day-old pigs reversed diabetes more efficiently than islets from other groups, we further evaluated the function of these islets post-transplantation. B6 rag-/- mouse recipients of various numbers of islets from 7-day-old pigs achieved normoglycemia faster and showed significantly improved response to glucose challenge compared to the recipients of the same numbers of islets from 3-day-old pigs. These results are in line with the findings that islets from 7-day-old pigs showed reduced voltage-dependent K+ (Kv) channel activity and their ability to recover from post-hypoxia/reoxygenation stress. Despite more resident immune cells and immunogenic characteristics detected in islets from 7-day-old pigs compared to islets from 3-day-old pigs, the combination of anti-LFA-1 and anti-CD154 monoclonal antibodies are equally effective at preventing the rejection of islets from both age groups of pigs. Collectively, these results suggest that islets from various ages of neonatal pigs vary in yield, cellular composition, and function. Such parameters may be considered when defining the optimal pancreas donor for islet xenotransplantation studies.

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“…Ucn3 KO mice were recently generated and reported to have no deficit in beta cell maturation or function, deeming Ucn3 a marker, but not a driver of maturation (Huang et al, 2020). Many other maturation markers have been postulated through studies of mouse development, human diabetes, or by studying human SC-islets, but lack corresponding evaluation comparing mature adult vs. immature fetal human tissues (Zito et al, 2010;Veres et al, 2019;Barsby and Otonkoski, 2022). Arda et al provided an important resource with their 2016 publication assessing single-cell human beta cell transcriptomes, identifying several genes that significantly change expression during early postnatal development (Arda et al, 2016).…”

Section: Open Access Edited Bymentioning

confidence: 99%

Validating expression of beta cell maturation-associated genes in human pancreas development

Tremmel

Mikat²,

Gupta³

et al. 2023

Front. Cell Dev. Biol.

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The identification of genes associated with human pancreatic beta cell maturation could stimulate a better understanding of normal human islet development and function, be informative for improving stem cell-derived islet (SC-islet) differentiation, and facilitate the sorting of more mature beta cells from a pool of differentiated cells. While several candidate factors to mark beta cell maturation have been identified, much of the data supporting these markers come from animal models or differentiated SC-islets. One such marker is Urocortin-3 (UCN3). In this study, we provide evidence that UCN3 is expressed in human fetal islets well before the acquisition of functional maturation. When SC-islets expressing significant levels of UCN3 were generated, the cells did not exhibit glucose-stimulated insulin secretion, indicating that UCN3 expression is not correlated with functional maturation in these cells. We utilized our tissue bank and SC-islet resources to test an array of other candidate maturation-associated genes, and identified CHGB, G6PC2, FAM159B, GLUT1, IAPP and ENTPD3 as markers with expression patterns that correlate developmentally with the onset of functional maturation in human beta cells. We also find that human beta cell expression of ERO1LB, HDAC9, KLF9, and ZNT8 does not change between fetal and adult stages.

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Maturation of beta cells: lessons from in vivo and in vitro models

Cited by 29 publications

References 151 publications

Single-cell RNA sequencing combined with single-cell proteomics identifies the metabolic adaptation of islet cell subpopulations to high-fat diet in mice

Single-cell RNA sequencing combined with single-cell proteomics identifies the metabolic adaptation of islet cell subpopulations to high-fat diet in mice

Yield, cell composition, and function of islets isolated from different ages of neonatal pigs

Validating expression of beta cell maturation-associated genes in human pancreas development

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