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RNA-seq analysis in residual pancreatic β-cells of Bmal1KO/DTA mice following massive ablation

ABSTRACT: We aimed to fill the gap in understanding functional roles of the islet cellular oscillators under diabetic conditions following massive β-cell ablation, and during β-cell regeneration. We assessed diurnal regulation of β-cell proliferation and transcriptional landscape in separated α- and residual β-cells -utilizing rtTA/TET-DTA mouse model that bears α- and β-cell specific labeling. Acute hyperglycemia and loss of β-cell mass perturbed absolute expression levels and temporal transcriptome profiles in residual β-cells, whereas in neighboring α-cells only changes in temporal profiles were observed. Strikingly, compensatory regeneration of β-cells exhibited circadian rhythmicity. In arrhythmic BMAL1 knockout mice, massive β-cell ablation led to aggravated hyperglycemia, hyperglucagonemia and a fatal non-compensated diabetes. No activation of β-cell regeneration via entry into cell-cycle was observed in arrhythmic mice, suggesting essential role of functional circadian clocks in this process.

ORGANISM(S): Mus musculus

PROVIDER: GSE151338 | GEO | 2020/10/01

REPOSITORIES: GEO

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Project description:Objective: The loss of insulin-secreting β-cells, ultimately characterizing most diabetes forms, demands the development of cell replacement therapies. The common endpoint for all ex vivo strategies is transplantation into diabetic patients. However, the effects of hyperglycemia environment on the transplanted cells were not yet properly assessed. Thus, the main goal of this study was to characterize global effect of brief and prolonged in vivo hyperglycemia exposure on the cell fate acquisition and maintenance of transplanted human pancreatic progenitors. Methods: To rigorously study the effect of hyperglycemia, in vitro differentiated human induced pluripotent stem cells (hiPSC)-derived pancreatic progenitors were xenotransplanted in normoglycemic and diabetic NSG RIP-DTR mice. The transplants were retrieved after one-week or one-month exposure to overt hyperglycemia and analyzed by large-scale microscopy or global proteomics. For this study we pioneer the use of the NSG RIP-DTR system in the transplantation of hiPSC, making use of its highly reproducible specific and absolute β-cell ablation property in the absence of inflammation or other organ toxicity. Results: Here we show for the first time that besides the presence of an induced oxidative stress signature, the cell fate and proteome landscape response to hyperglycemia was different, involving largely different mechanisms, according to the period spent in the hyperglycemic environment. Surprisingly, brief hyperglycemia exposure increased the bihormonal cell number by impeding the activity of specific islet lineage determinants. Moreover it activated antioxidant and inflammation protection mechanisms signatures in the transplanted cells. In contrast, the prolonged exposure was characterized by decreased numbers of hormone+ cells, low/absent detoxification signature, augmented production of oxygen reactive species and increased apoptosis. Conclusion: Hyperglycemia exposure induced distinct, period-dependent, negative effects on xenotransplanted human pancreatic progenitor, affecting their energy homeostasis, cell fate acquisition and survival.

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RNA-seq analysis in residual pancreatic β-cells of Bmal1KO/DTA mice following massive ablation

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