The molecular and morphogenetic basis of pancreas organogenesis

Abstract

The pancreas is an essential endoderm-derived organ that ensures nutrient metabolism via its endocrine and exocrine functions. Here we review the essential processes governing the embryonic and early postnatal development of the pancreas discussing both the mechanisms and molecules controlling progenitor specification, expansion and differentiation. We elaborate on how these processes are orchestrated in space and coordinated with morphogenesis. We draw mainly from experiments conducted in the mouse model but also from investigations in other model organisms, complementing a recent comprehensive review of human pancreas development (Jennings et al., 2015) [1]. The understanding of pancreas development in model organisms provides a framework to interpret how human mutations lead to neonatal diabetes and may contribute to other forms of diabetes and to guide the production of desired pancreatic cell types from pluripotent stem cells for therapeutic purposes.

Introduction

The pancreas is a compound exocrine and endocrine gland located retroperitoneally in the abdominal cavity. The concerted functions of the exocrine and endocrine compartment are essential in systemic nutrient metabolism, as they facilitate digestion of nutrients and the subsequent regulation of blood glucose homeostasis, respectively. The exocrine pancreas consists of acinar cells organized into acini at the terminal ends of an elaborate network of ductal cells. The acinar cells secrete proenzymes catalyzing the breakdown of carbohydrates, proteins and lipids following their proteolytic activation after secretion to the duodenum. Proenzymes secreted by the acinar cells are transported via a highly branched network of hydrogen bicarbonate-producing ductal cells converging into sequentially larger ducts, eventually mediating the secretion of the enzyme-rich pancreatic fluid through the main pancreatic duct of Wirsung and the accessory duct of Santorini into the duodenum. The acinar cells make up the bulk of the pancreas, constituting as much as 90% of the organ. Interspersed between the acinar tissue, the endocrine compartment of the pancreas is organized into the highly vascularized and innervated discrete islets of Langerhans, comprising about 1–2% of the pancreas. The islets of Langerhans are composed of five different endocrine cellular subtypes producing different peptide-based hormones. These hormones regulate nutrient metabolism through systemic processes such as blood glucose homeostasis, coordination of digestion and appetite [2].

The systemic nature of the processes regulated by the pancreas is reflected by the considerable morbidity and mortality associated with debilitating pancreatic diseases such as diabetes mellitus, pancreatitis and pancreatic cancer. Driven by the desire to understand the underlying pathology and develop therapeutic strategies for these diseases, the mechanisms governing pancreas development have been extensively studied. Recent advances in generating insulin-producing cells from stem cell sources have spurred the optimism of a cell-based therapy for diabetes [3], [4], [5]. Since such differentiation protocols rely on an informed approach from developmental biology, increasing the knowledge of mechanisms governing cell fate decisions during embryonic and perinatal pancreas organogenesis might prove essential in the identification of control parameters for in vitro cell differentiation or reinstatement of differentiation- and proliferative control in pancreatic cancer. Here we review the essential processes governing embryonic and perinatal development of the pancreas with special emphasis on the mechanisms controlling cell fate allocation during murine pancreas organogenesis. We draw mainly from experiments conducted in the mouse model but also from investigations in other model organisms, complementing a recent comprehensive review of human pancreas development [1].