Butyrate and Class I Histone Deacetylase Inhibitors Promote Differentiation of Neonatal Porcine Islet Cells into Beta Cells.

Yichen Zhang,Yichen Zhang,Elisabeth Kemter,Elisabeth Kemter,Elisabeth Kemter,Elisabeth Kemter,Yutian Lei,Yutian Lei,Eckhard Wolf,Eckhard Wolf,Eckhard Wolf,Eckhard Wolf,Jochen Seissler,Mohsen Honarpisheh,Mohsen Honarpisheh

doi:10.3390/cells10113249

Abstract

Neonatal porcine islets-like clusters (NPICCs) are a promising source for cell therapy of type 1 diabetes. Freshly isolated NPICCs are composed of progenitor cells and endocrine cells, which undergo a maturation process lasting several weeks until the normal beta cell function has developed. Here, we investigated the effects of short-chain fatty acids on the maturation of islet cells isolated from two to three day-old piglets. NPICCs were cultivated with acetate, butyrate and propionate (0–2000 µM) for one to eight days. Incubation with butyrate resulted in a significant upregulation of insulin gene expression and an increased beta cell number, whereas acetate or propionate had only marginal effects. Treatment with specific inhibitors of G-protein-coupled receptor GPR41 (β-hydroxybutyrate) and/or GPR43 (GPLG0974) did not abolish butyrate induced insulin expression. However, incubation of NPICCs with class I histone deacetylase inhibitors (HDACi) mocetinostat and MS275, but not selective class II HDACi (TMP269, MC1568) mimicked the butyrate effect on beta cell differentiation. Our study revealed that butyrate treatment has the capacity to increase the number of beta cells, which may be predominantly mediated through its HDAC inhibitory activity. Butyrate and specific class I HDAC inhibitors may represent beneficial supplements to promote differentiation of neonatal porcine islet cells towards beta cells for cell replacement therapies.

Highlights

Type 1 diabetes (T1D) is a chronic autoimmune disease leading to the complete destruction of insulin-producing beta cells
We investigated the potential of SCFAs to optimize NPICC culture conditions and promote differentiation of islets into insulin-positive porcine beta cells
NPICCs from day three after isolation for one to eight days in our regular culture medium (B-IC medium), or in medium supplemented with 100–2000 μM acetate, butyrate and propionate, respectively

Summary

Introduction

Type 1 diabetes (T1D) is a chronic autoimmune disease leading to the complete destruction of insulin-producing beta cells. Clinical studies have shown that islet cell transplantation is an effective treatment option in some patients with T1D. The clinical application of pancreas and islet cells transplantation is limited by the shortage of organ donors and problems in the isolation of large numbers of high quality islets from organ donors [1]. Porcine islets are a promising source for islet cell replacement therapies due to the high similarity in the regulation of glucose homeostasis as compared to human islets, the unlimited availability and the novel molecular techniques to generate less immunogenic porcine tissues by genetic engineering of donor pigs [2,3,4]. Previous studies have demonstrated that pancreata from neonatal, pre-weaning piglets have several advantages over adult pigs, including an easier isolation process to yield high quality islets and lower costs [5,6,7]. Neonatal porcine islets-like clusters (NPICCs) are immature with respect to

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