Betacellulin inhibits amylase and glucagon production and promotes beta cell differentiation in mouse embryonic pancreas

Abstract

Aims/hypothesis Betacellulin, a member of the epidermal growth factor family, is expressed in the pancreas and is thought to regulate differentiation of beta cells during development. The aim of the present study was to investigate the effects of exogenous betacellulin on the development of the mouse embryonic pancreas. Materials and methods We used an in vitro culture model system based on the isolation and culture of the dorsal embryonic pancreas from day 11.5 embryos. Cultures were treated for up to 10 days with 10 ng/ml betacellulin and then analysed for changes in the expression of pancreatic exocrine, endocrine and ductal markers. Results Pancreases developed in culture and expressed the full complement of exocrine (both acinar and ductal) and endocrine cell types. Betacellulin enhanced branching morphogenesis and the proliferation of mesenchyme, increased Pdx1 and insulin production and inhibited the production of the exocrine cell marker amylase and the endocrine hormone glucagon. Conclusions/interpretation These results suggest betacellulin has distinct and separate effects on exocrine, endocrine and ductal differentiation. In the future, betacellulin could perhaps be utilised to increase the production of beta cells from embryonic pancreatic tissue for therapeutic transplantation.

Generation of Functional Human Pancreatic β Cells In Vitro

“…And previous studies had shown that these PDX1+/NKX6-1+ pancreatic progenitors (PP2) could be further differentiated in vitro into some INS+ cells along with INS+/GCG+ or INS+/SST+ polyhormonal (PH) cells (Nostro et al, 2011; Rezania et al, 2012; Thowfeequ et al, 2007; Aguayo-Mazzucato et al, 2013; D’Amour et al, 2006; Hrvatin et al, 2014). We use the nomenclature PH (polyhormonal, Figure 1A) to refer to this cell population of in vitro differentiated hPSCs.…”

Origin of pancreatic endocrine cells from biliary duct epithelium

“…Transgenic mice overexpressing EGF under the insulin promoter showed an increased islet size and frequency of insulin positive cells in murine pancreatic ducts [46]. However, similar experiments on EGF treated pancreatic buds suggested that EGF might stimulate epithelial proliferation and thereby inhibit differentiation of pancreatic precursors to b-cells [47,48]. LIF is known to be expressed in pancreatic ducts [28], but evidence of its endogenous functions in pancreatic development are lacking.…”

Extrinsic Factors Involved in the Differentiation of Stem Cells into Insulin-Producing Cells: An Overview

“…For example, Sun et al showed that combined use of betacellulin and activin A was involved in the differentiation of bone marrow-derived mesenchymal stem cells from diabetic patients into IPCs [35]. On the other hand, Thowfeequ et al demonstrated that betacellulin inhibited amylase and glucagon production and promoted beta cell differentiation in mouse embryonic pancreas [74]. Using betacellulin and/or activin A, other studies have successfully differentiated stem cells of liver [40] and pancreatic [54] origins into IPCs.…”