Dataset Information

Chronically elevated exogenous glucose elicits antipodal effects on the proteome signature of differentiating human pancreatic progenitors

ABSTRACT: The past decade revealed that cell identity changes, such as dedifferentiation or transdifferentiation, accompany the insulin-producing β-cell decay in most diabetes conditions. Mapping and controlling the mechanisms governing these processes is thus extremely valuable for managing the disease progression. Extracellular glucose is known to impact cell identity by impacting the redox balance. Here we use global proteomics and pathway analysis to map the response of differentiating human pancreatic progenitors to chronically increased in vitro glucose levels. We show that exogenous high glucose levels impact different protein subsets in a concentration-dependent manner. In contrast, regardless of concentration, high exogenous glucose elicits an antipodal effect on the proteome landscape, inducing both beneficial and detrimental changes in regard to achieving the desired islet cell fingerprint. Furthermore, we identified that only a subgroup of these effects and pathways are regulated by changes in redox balance. Our study highlights a complex yin-yang action of exogenous glucose on differentiating pancreas progenitors with a distinct proteome signature.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Stem Cell, Cell Culture

SUBMITTER: Thomas Aga Legøy

LAB HEAD: Simona Chera

PROVIDER: PXD022177 | Pride | 2021-09-09

REPOSITORIES: Pride

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			Action	DRS
	414286_m23185_TomHum.mzIdentML	Mzid
	414287_m23184_TomHum.mzIdentML	Mzid
	414288_m23183_TomHum.mzIdentML	Mzid
	414289_m23182_TomHum.mzIdentML	Mzid
	414290_m23181_TomHum.mzIdentML	Mzid

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Chronically Elevated Exogenous Glucose Elicits Antipodal Effects on the Proteome Signature of Differentiating Human iPSC-Derived Pancreatic Progenitors.

Ghila Luiza L Legøy Thomas Aga TA Mathisen Andreas Frøslev AF Abadpour Shadab S Paulo Joao A JA Scholz Hanne H Ræder Helge H Chera Simona S

International journal of molecular sciences 20210402 7

The past decade revealed that cell identity changes, such as dedifferentiation or transdifferentiation, accompany the insulin-producing β-cell decay in most diabetes conditions. Mapping and controlling the mechanisms governing these processes is, thus, extremely valuable for managing the disease progression. Extracellular glucose is known to influence cell identity by impacting the redox balance. Here, we use global proteomics and pathway analysis to map the response of differentiating human pan ...[more]

PMID: 33918250

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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.