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Paracrine stimulation effect of human salispheres on mouse salivary gland

ABSTRACT: Human salispheres, a culture of stem/progenitor cells, represent a potential therapy for radiation induced hyposalivation. Radiation-induced hyposalivation dramatically reduces quality of life of patients. We have demonstrated the potential of human salispheres to engraft and differentiate when transplanted into a mouse model of hyposalivation, in the manuscript associated with these data. We also demonstrate the functional recovery of irradiated salivary glands (SGs) following human salisphere transplantation, by the measurement of saliva production. When analyzing human salisphere- transplanted SGs for the presence of human cells, we noted that the highest proportion of human cells were present 1 week after transplantation. This microarray study was designed to determine if paracrine signaling from transplanted human salisphere cells to recipient mouse SGs accounts for a part of the functional recovery of the recipient SG we observe. We compare the transcriptome from irradiated control SG of immunecompromised NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice with that of NSG SGs transplanted with 100,000 human salisphere cells. All mice were sacrificed 1 week following transplantation (or non-transplantation in case of controls) and Illumina array chips used to detect differences in gene expression.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE72869 | GEO | 2015/09/10

SECONDARY ACCESSION(S): PRJNA295221

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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Paracrine stimulation effect of human salispheres on mouse salivary gland

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