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Development of the Pancreas and Related Structures

Brian Lewis and Junhao Mao

Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA

Anatomy of the Pancreas

The pancreas is a unique exocrine and endocrine organ located in the retroperitoneal region of the upper abdominal cavity. In humans, when fully formed, the organ has a distinct head, body, and tail, with the head of the pancreas contacting the duodenal region of the intestines (the main pancreatic duct drains into the duodenum) and the tail of the pancreas abutting the spleen. The greatest mass of the organ is present in the head, which is composed of tissue derived from two independent anlagen (see later). In other mammals, such as dogs and mice, the organ has a far less distinct structure and is identified as an amorphous pink tissue adjacent to the mesentery that runs along the upper intestinal wall.

The cells of the pancreas are arranged into distinct lobules composed primarily of the digestive enzyme-producing cells of the exocrine pancreas, which are arranged into acini (so-called acinar cells), the ductal structures that conduct these digestive enzymes to the intestines, and distinct clusters of endocrine cells, the islets of Langerhans, that secrete hormones and function to regulate glucose uptake and release and serum glucose levels. There are five recognized cell types within the islets, the a, ß, d, e, and PP cells, which produce the hormones glucagon, insulin, somatostatin, ghrelin, and pancreatic polypeptide, respectively. The majority of the pancreatic tissue mass (more than 90-95%) is present within the exocrine compartment of the organ, with the islets of Langerhans, scattered throughout the tissue. The pancreas also has connective tissue, derived from the embryonic mesenchyme, which forms the septa that separate the many lobules of the organ. Mesenchyme-derived stromal cells are also present in the interlobular regions surrounding the pancreatic ducts, blood vessels, and nerves. In the following sections, we explore how these disparate cell types come together to form the pancreas.

Organogenesis in the Region of the Pancreas

Around day 14, the embryonic bilaminar germ disk is composed of a layer of epiblast and a layer of hypoblast. At this time, a faint groove appears along the longitudinal midline of the germ disk that develops into a structure called the primitive streak [1]. Around day 15, epiblast cells near the primitive streak undergo a morphologic change and migrate through the primitive streak into the space between the epiblast and hypoblast in a process known as gastrulation (Fig. 1.1). Some of the ingressing epiblast cells invade the hypoblast, which is eventually replaced by a new layer of epiblast-derived cells known as the definitive endoderm. Additional migrating epiblast cells occupy the space between the epiblast and the definitive endoderm to form a third layer of cells called the intraembryonic mesoderm (Fig. 1.1). As cells of the germinal disk migrate anteriorly to form a head process and lateral regions roll underneath to form an approximately cylindrical body shape, the endoderm is rolled into a tube that projects into the developing head region of the embryo surrounded by the mesoderm layer. This is the primitive digestive tube. The pancreas is specified by two separate outgrowths that arise on the dorsal and ventral surfaces of the primitive digestive tube. The epithelial cells of the pancreas originate from the interior lining of the primitive gut tube, which consists of a single layer of endoderm. A layer of mesenchyme, from which the muscle and connective tissue of the gastrointestinal organs are derived, surrounds the endoderm.

Figure 1.1 Germ disks sectioned through the region of the primitive streak, showing gastrulation. (a) On days 14 and 15, the ingressing epiblast cells replace the hypoblast to form the definitive endoderm. (b) The epiblast that ingresses on day 16 migrates between the endoderm and epiblast layers to form the intraembryonic mesoderm.

Source: Larsen 2001 [1]. Reproduced with permission of Elsevier.

The anterior regions of the endoderm form the foregut; regions posterior to the foregut form the midgut and hindgut. The most anterior regions of the foregut give rise to the esophagus and stomach. Just posterior to the foregut, the endoderm is continuous with the yolk sac, which extends outside the embryo, in a region known as the anterior intestinal portal. Endodermally derived cells close to the anterior intestinal portal specify the pancreas. The duodenum and liver are also specified by foregut endoderm in this region.

Thus, many gastrointestinal tissues are specified at the same time from a fairly restricted region of the gut endoderm. How are each of these organs specified in the appropriate anatomic location, and how do they differentiate properly into mature functional organs? The epithelial organs of the developing embryo originate as buds from the endoderm as the appropriate temporal and spatial cues are received. Thus, proper initiation and location of endodermally derived organs are regulated by the activation status of important signal transduction pathways involved in animal development, including the hedgehog, Notch, and fibroblast growth factor (FGF) signaling pathways.

Early Pancreatic Development

During the fourth week of gestation, two buds appear on the dorsal and ventral sides of the foregut near the anterior intestinal portal. These epithelial buds indicate the specification of the pancreas. These buds initially grow and differentiate independently, but later fuse to form a single organ. The anlage on the dorsal side, the dorsal pancreatic bud, appears first and gives rise to the dorsal pancreas. The cells of the dorsal pancreas will give rise to the head, body, and tail of the mature pancreas. The second pancreatic anlage appears shortly after the appearance of the dorsal pancreatic bud. This bud, which appears on the ventral side of the gut tube, is appropriately called the ventral pancreatic bud and develops into the ventral pancreas, which forms part of the head of the pancreas. Both pancreatic buds develop simultaneously, and the proliferating epithelial cells grow as projections into the surrounding mesenchymal tissue. During this time, the development of the intestines, and importantly the duodenum, continues. Rotation and asymmetric growth of the duodenum move the originally ventral part to a dorsal location, carrying with it the ventral pancreas and the primordial common bile duct. As the duodenum begins to rotate into its appropriate anatomic location, the ventral pancreas also rotates around the gut tube such that the ventral and dorsal pancreata lie adjacent to each other. These pancreatic rudiments then fuse to form a single organ. While both developing pancreatic buds independently form pancreatic ducts, the lumens of which are continuous with the lumen of the primitive gut, after they fuse their primary ducts anastomose to form the main pancreatic duct (Fig. 1.2). The region of the primary duct of the ventral pancreas proximal to the duodenum fuses with the primary duct of the dorsal pancreas and becomes the primary drainage into the duodenum, entering the duodenum immediately adjacent to the common bile duct. The proximal region of the primary duct of the dorsal pancreas sometimes remains as an accessory drainage but often regresses. The ducts sometimes fail to fuse, in which event two independent duct systems drain into the duodenum.

Figure 1.2 Contributions of the dorsal and ventral pancreas to the definitive organ. The ventral pancreas becomes most of the head. The dorsal pancreas becomes the remainder of the head, plus the body and tail. The duct of the dorsal pancreas contributes a large part of the main pancreatic duct plus the accessory duct. The duct of the ventral pancreas becomes the part of the main duct nearest the duodenum.

Signaling Governing Early Pancreatic Development

Early pancreatic development and establishing pancreatic identity are governed by the interplay between several critical transcription factors and intercellular signaling pathways. PDX1 and PTF1A are among the earliest transcription factors expressed in the pancreatic progenitor populations, and their functions are critical for pancreatic development [2-5]. In mice, PDX1 expression is first detected in the primitive gut tube at embryonic day 8.5 (E8.5), which corresponds to ~25-27 days in humans. PDX1 expression demarcates the prospective pancreatic domain, which is then followed by PTF1A expression in pancreatic endoderm at E9.5 [5-7]. Mice lacking either transcription factor display pancreatic agenesis [2, 3, 5, 8].

In addition to the transcription factors, several key intercellular signaling pathways between gut endoderm and mesenchyme, including the hedgehog, FGF, Notch and Hippo pathways, play important roles in establishing the pancreatic identity and controlling the expression of these transcription factors. Research studies have shown that sonic hedgehog (SHH), the ligand of the hedgehog pathway, is excluded from the prospective pancreatic region, but is present in the region of foregut that becomes the duodenum, and ectopic expression of SHH in the pancreas induces an intestinal fate, suggesting...