Fol. Biol. 2012, 58, 98-105
Activation of the Jak/Stat Signalling Pathway by Leukaemia Inhibitory Factor Stimulates Trans-differentiation of Human Non-Endocrine Pancreatic Cells into Insulin-Producing Cells
Differentiation of pancreatic β-cells is regulated by a wide range of signalling pathways. The aim of our current work was to evaluate the effect of the Jak/Stat signalling pathway on the differentiation of human non-endocrine pancreatic cells into insulin-producing cells. Activation of the Jak/Stat signalling pathway by leukaemia inhibitory factor (LIF) stimulated differentiation of C-peptide-negative human non-endocrine pancreatic cells into insulin-producing cells in 6.3 ± 2.0 % cells (N = 5) and induced expression of pro-endocrine transcription factor neurogenin 3, Notch signalling pathway suppressor HES6 and stimulator of β-cell neogenesis REG3A. The expression of the REG3A gene and increased rate of differentiation into insulin-producing cells (10.2 ± 2.1 %) were further stimulated by a combination of LIF with nicotinamide and dexamethasone. Glucose-stimulated (5 vs. 20 mM) C-peptide secretion confirmed proper insulin secretory function of trans-differentiated insulin-producing cells (0.51 vs. 2.03 pmol C-peptide/μg DNA, P < 0.05). Our results indicate that Jak/Stat signalling critically contributes to trans-differentiation of non-endocrine pancreatic cells into functional insulin-producing cells. The positive effect of the Jak/Stat signalling pathway on trans-differentiation is mediated by the key genes that activate differentiation of pancreatic β-cells.
Keywords
diabetes mellitus, insulin, pancreas, beta cell, islets, stem cells, leukaemia inhibitory factor, differentiation, Notch, Jak/Stat.
Funding
This study was supported by Grant NS/9712-4/2008 from the Internal Grant Agency of the Ministry of Health, Czech Republic.
References
Copyright
This is an open-access article distributed under the terms of the Creative Commons Attribution License.
