MARKERS IN EXPANSION OF REGENERATING & EARLY POSTNATAL PANCREAS

Abstract

Type 1 diabetes results from destruction of insulin‐producing pancreatic beta cells. A possible treatment is to replace these cells by genetic engineering or the use of stem cells. This approach requires that we understand the signals that regulate beta cell proliferation. Inhibition of DNA binding proteins (Ids), are implicated in a number of cellular processes, including control of proliferation and differentiation. Ids bind to and inhibit the function of bHLH transcription factors including those that regulate pancreatic development. Moreover, bone morphogenetic proteins (BMPs) are shown to regulate the expression of Ids. We found that neutralization of BMP4 significantly reduced duct epithelial cell expansion in a mouse model of islet regeneration. BMP4 stimulation promotes Id2 binding to the bHLH transcription factor NeuroD, which is required for the differentiation of pancreatic islet cells. Moreover, using BTC cells we demonstrated that Id2 enhanced proliferation through the Rb/E2F pathway. The early postnatal pancreas represents an intriguing model since expansion of beta cells is still evident. We found BMP4 enhanced two surface markers that may be relevant in proliferation in neonatal pancreatic cells and during islet regeneration. Collectively, our data provide novel insights into the signaling pathways required for beta cell proliferation, which may be useful for treating diabetes.