The Effect of Epigenetic Factors on Differentiation of Pancreatic Progenitor Cells Into Insulin-Producing Cells

• Published in: Transplantation proceedings Vol. 43; no. 9; pp. 3212 - 3216
• Main Authors: Leontovyč, I, Koblas, T, Pektorova, L, Zacharovova, K, Berkova, Z, Saudek, F
• Format: Journal Article Conference Proceeding
• Language: English
• Published: Amsterdam Elsevier Inc 01.11.2011; Elsevier
• Subjects: Azacitidine - analogs & derivatives; Azacitidine - pharmacology; Azepines - metabolism; Biological and medical sciences; C-Peptide - chemistry; Cell Culture Techniques - methods; Cell Differentiation - drug effects; Epigenesis, Genetic; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Humans; Hydroxamic Acids - pharmacology; Immunohistochemistry - methods; Insulin-Secreting Cells - cytology; Islets of Langerhans; Keratin-19 - biosynthesis; Medical sciences; Models, Biological; Models, Genetic; Pancreas - metabolism; Pyrroles - pharmacology; Quinazolines - metabolism; Stem Cells - cytology; Surgery; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Tissue, organ and graft immunology; Transcription Factors; Pancreatic hormone; Stem cell; Transplantation; Cell differentiation; Insulin; Medicine; Treatment; Surgery; Epigenetics; Graft; Differentiation; Pancreas; Progenitor cell
• ISSN: 0041-1345; 1873-2623
• DOI: 10.1016/j.transproceed.2011.10.025

Abstract Differentiation of pancreatic progenitors into insulin-producing β cells is regulated by various transcription factors. To be expressed the genes coding these transcription factors need to be in accessible DNA. Whether a particular gene is present in a form of active euchromatin structure with accessible DNA or in an inactive heterochromatin structure with inaccessible DNA is determined by various epigenetic modifications. We studied the effect of epigenetic modifiers on differentiation of human nonendocrine cells into insulin-producing cells with the aim to evaluate the effect of epigenetic modifications in that process. Within 3 days of cultivation nonendocrine cells form isletlike cell clusters (ILCCs) containing mainly cytokeratin-19-positive cells. After cultivation with epigenetic modifiers and further differentiation, the highest number of C-peptide-positive cells (10.3% ± 2.9%) as well as glucagon-positive cells (7.2% ± 2.8%) was observed in a sample supplemented with a combination of 5-Aza-2′-deoxycytidine modifiers, BIX01294 and MC1568. In response to glucose stimulation (5 vs 20 mmol/L) these ILCCs secreted increased amounts of C-peptide (0.45 vs 1.05 pmol C-peptide/μg DNA). Control samples treated without any epigenetic modifiers showed significantly lower numbers of C-peptide-positive cells (3.5% ± 1.6%). These results showed that a combination of epigenetic modifiers 5-Aza-2′-deoxycytidine (BIX01294 and MC1568) significantly improved reproducible differentiation of nonendocrine pancreatic cells into insulin-producing cells.