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Maturation of human embryonic stem cell-derived pancreatic progenitors into functional islets capable of treating pre-existing diabetes in mice.

ABSTRACT: Diabetes is a chronic debilitating disease that results from insufficient production of insulin from pancreatic β-cells. Islet cell replacement can effectively treat diabetes but is currently severely limited by the reliance upon cadaveric donor tissue. We have developed a protocol to efficiently differentiate commercially available human embryonic stem cells (hESCs) in vitro into a highly enriched PDX1+ pancreatic progenitor cell population that further develops in vivo to mature pancreatic endocrine cells. Immature pancreatic precursor cells were transplanted into immunodeficient mice with streptozotocin-induced diabetes, and glycemia was initially controlled with exogenous insulin. As graft-derived insulin levels increased over time, diabetic mice were weaned from exogenous insulin and human C-peptide secretion was eventually regulated by meal and glucose challenges. Similar differentiation of pancreatic precursor cells was observed after transplant in immunodeficient rats. Throughout the in vivo maturation period hESC-derived endocrine cells exhibited gene and protein expression profiles that were remarkably similar to the developing human fetal pancreas. Our findings support the feasibility of using differentiated hESCs as an alternative to cadaveric islets for treating patients with diabetes.

SUBMITTER: Rezania A

PROVIDER: S-EPMC3402300 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:AimsThe transcriptome of different dissociated pancreatic islet cells has been described in enzymatically isolated islets in both health and disease. However, the isolation, culturing, and dissociation procedures likely affect the transcriptome profiles, distorting the biological conclusions. The aim of the current study was to characterize the cells of the islets of Langerhans from subjects with and without type 1 diabetes in a way that reflects the in vivo situation to the highest possible extent.MethodsIslets were excised using laser capture microdissection directly from frozen pancreatic tissue sections obtained from organ donors with (n = 7) and without (n = 8) type 1 diabetes. Transcriptome analysis of excised samples was performed using AmpliSeq. Consecutive pancreatic sections were used to estimate the proportion of beta-, alpha-, and delta cells using immunofluorescence and to examine the presence of CD31 positive endothelial regions using immunohistochemistry.ResultsThe proportion of beta cells in islets from subjects with type 1 diabetes was reduced to 0% according to both the histological and transcriptome data, and several alterations in the transcriptome were derived from the loss of beta cells. In total, 473 differentially expressed genes were found in the islets from subjects with type 1 diabetes. Functional enrichment analysis showed that several of the most upregulated gene sets were related to vasculature and angiogenesis, and histologically, vascular density was increased in subjects with type 1 diabetes. Downregulated in type 1 diabetes islets was the gene set epithelial mesenchymal transition.ConclusionA number of transcriptional alterations are present in islets from subjects with type 1 diabetes. In particular, several gene sets related to vasculature and angiogenesis are upregulated and there is an increased vascular density, suggesting an altered microvasculature in islets from subjects with type 1 diabetes. By studying pancreatic islets extracted directly from snap-frozen pancreatic tissue, this study reflects the in vivo situation to a high degree and gives important insights into islet pathophysiology in type 1 diabetes.

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Maturation of human embryonic stem cell-derived pancreatic progenitors into functional islets capable of treating pre-existing diabetes in mice.

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