Insulin-producing cells derived from human pancreatic non-endocrine cell cultures reverse streptozotocin-induced hyperglycaemia in mice

Zhao, M., Amiel, S. A., Christie, Michael R., Rela, M., Heaton, N. and Huang, G. C. (2005) Insulin-producing cells derived from human pancreatic non-endocrine cell cultures reverse streptozotocin-induced hyperglycaemia in mice. Diabetologia, 48 (10). pp. 2051-2061. ISSN 0012-186X

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Insulin-producing cells derived from human pancreatic non-endocrine cell cultures reverse streptozotocin-induced hyperglycaemia in mice

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Abstract

Aims/hypothesis: The aim of the study was to investigate the potential of human pancreatic non-endocrine cells to transdifferentiate into endocrine cells that would be capable of secreting insulin in response to glucose and ameliorating insulin-deficient diabetes after transplantation. Materials and methods: Cell fractions enriched with exocrine cells after human islet isolation were treated with streptozotocin to remove residual beta cells, grown in monolayer culture to allow de-differentiation, transferred to cluster culture for redifferentiation in the presence of activin A, betacellulin, nicotinamide and glucose, supplemented with 10 FCS, and administered to streptozotocin- induced diabetic SCID mice. A subset of cells was transfected with the IPF1 gene (also known as PDX1) before transdifferentiation. Results: No insulin was detectable in cell preparations after 5 days of treatment with streptozotocin. In monolayer culture, 90 of the streptozotocin-treated pancreatic cells co-expressed cytokeratin-19 and vimentin at 2 weeks and 60 expressed nestin at 4 weeks. Cell cultures with a high proportion of nestin-expressing cells had greater plasticity for transdifferentiation into cells with phenotypic and functional markers of beta cells, this property being significantly enhanced by transfection with IPF1 gene and leading to 15±6.7 insulin-positive cells after transplantation vs. 0.01 of cells transplanted after streptozotocin treatment alone. These cells improved glucose control in all of 42 diabetic mice after transplantation, restoring normoglycaemia in 40. Conclusions/ interpretation: Human pancreatic cells are a potential source of new glucose-responsive insulin-producing cells that may be developed further for clinical use. © Springer-Verlag 2005.

Keywords:activin A, betacellulin, biological marker, cytokeratin, glucose, insulin, nestin, nicotinamide, transcription factor PDX 1, vimentin, animal experiment, animal model, article, cell culture, cell differentiation, cell fractionation, cell growth, cell isolation, controlled study, exocrine cell, genetic transfection, human, human cell, hyperglycemia, insulin release, male, monolayer culture, mouse, nonhuman, pancreas islet transplantation, phenotype, priority journal, protein expression, SCID mouse, streptozocin diabetes, treatment outcome, Adolescent, Adult, Animals, Biological Markers, Cell Proliferation, Cell Transplantation, Cells, Cultured, Diabetes Mellitus, Experimental, Female, Glucose Tolerance Test, Homeodomain Proteins, Humans, Mice, Mice, SCID, Middle Aged, Pancreas, Pancreas Transplantation, Plasmids, Reverse Transcriptase Polymerase Chain Reaction, Trans-Activators, Transfection
Subjects:A Medicine and Dentistry > A100 Pre-clinical Medicine
Divisions:College of Science > School of Life Sciences
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ID Code:18126
Deposited On:31 Jul 2015 09:38

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