Studies on the effects of short-chain fatty acids on beta cell differentiation and maturation in neonatal porcine islet-like cell clusters

Zhang, Yichen (2022): Studies on the effects of short-chain fatty acids on beta cell differentiation and maturation in neonatal porcine islet-like cell clusters. Dissertation, LMU München: Medizinische Fakultät

Abstract

Cell replacement therapy is a realistic option for the treatment and cure of type 1 diabetes. Neonatal porcine islets cell clusters (NPICCs) are considered to represent an unlimited cell source but face some challenges including the strong immunogenicity and the need for the generation of high numbers of excellent quality NPICCs. Since NPICCs are composed of progenitor cells and immature insulin-secreting beta cells, novel strategies to improve in vitro generation of matured beta cells and/or to increase islet numbers is a prerequisite for the near future transfer of xenotransplantation to the clinic. In the present study, NPICCs were isolated from 2-3 days-old piglets to evaluate the effects of three main short-chain fatty acids (SCFA), acetate, propionate and butyrate, on in vitro islet differentiation and beta cell function assessed by real-time quantitative PCR, FACS analysis, immunohistology and glucose-stimulated insulin secretion (GSIS). Butyrate promoted a significant time- and dose-dependent up-regulation in insulin gene expression and an increased beta cell number, whereas acetate or propionate only marginally influenced the beta cell phenotype. The treatment with specific inhibitors of SCFA receptors such as G-protein-coupled receptor GPR41 (β-hydroxybutyrate) and GPR43 (GPLG0974) did not suppress the butyrate-mediated increase of insulin expression. However, the application of specific class I histone deacetylase (HDAC) inhibitors mocetinostat, MS275, FK228 and RGFP996 mimicked butyrate on beta cell differentiation, whereas selective class II HDAC inhibitors (TMP269, MC1568) displayed no effects. These data suggest that the pro-endocrine impact of butyrate is mainly mediated through its HDAC inhibitory activity. The data of the present study suggest that butyrate and class I HDAC inhibitors are important agents to study the mechanisms of beta cell differentiation in porcine islets and produce optimized NPICC cell products for novel cell replacement therapies.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften ; 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Fakultäten: Medizinische Fakultät
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 27. Oktober 2022
• 1. Bericht­erstatter:in: Seißler, Jochen