The mammalian pancreas is a complex organ situated transversely across the posterior wall of the abdomen, behind the stomach. A diagram showing the anatomy and composition of the pancreas is shown in figure 1.
The pancreas is an unusual organ as it functions as both an exocrine and an endocrine gland, playing a central role in both food digestion as well as glucose homeostasis. Exocrine glands secrete enzymes into ducts that lead directly to the site of action. Endocrine glands secrete hormones directly into the blood stream where they can be transported around the body to their sites of action.
The majority of the pancreas is composed of pancreatic exocrine cells and their associated ducts. The exocrine tissue is made up of acinar cells that are arranged in grape-like clusters. These cells secrete digestive enzymes into an elaborate network of affiliated ducts that drain the secretions into the duodenum (the first section of the small intestine).
The endocrine portion of the pancreas contains 5 distinct hormone-producing cell types that are organised into clustered structures known as islets of Langerhans. These are made up of insulin-secreting beta (β) cells, glucose-secreting alpha (α) cells, somatostatin-producing delta (δ) cells, pancreatic polypeptide (PP) cells and, more recently discovered, ghrelin-secreting epsilon (ε) cells. The hormones secreted by the endocrine pancreas are absorbed directly into the blood through a vast capillary network that surrounds and infiltrates each islet structure.
During the 3rd week of gestation one of the most important events occurs, as the three germ layers; ectoderm, mesoderm and endoderm are established in the embryo; a process known as gastrulation (Figure 2). Over the next 3-8 weeks a period of organogenesis begins and each of the germ layers gives rise to a number of specific tissues and organs.
The ectoderm goes on to form the central and peripheral nervous systems, sensory epithelium of the ear, nose and eyes, as well as components of the skin. Supporting tissues, such as connective tissue, cartilage and bone are derived from the mesoderm. This layer also forms the musculature, blood and lymph systems and the walls of the heart and the kidneys and gonads, and their corresponding vessels. The endoderm layer initially forms the epithelial lining of the primitive gut tube. During further development organs of the digestive and respirative systems, including the lungs, liver, pancreas and urinary bladder, start to emerge from the tube and the endodermal cells become their epithelial lining (Figure 3).
The first visible evidence of the human pancreas is identified around 26 days post-conception (dpc) as a thickening on the dorsal aspect of the foregut epithelium. Six days later another outgrowth starts to develop on the opposite, ventral, side of the foregut. These projections are known as the dorsal and ventral buds. Over the next couple of weeks these buds elongate by a process of epithelial cell proliferation and migration. Rotation of the gut brings the two expanding buds together. They fuse to form a single organ at 56 dpc. The dorsal bud becomes the tail of the adult pancreas and the ventral bud becomes the ucinate process and pancreatic head. The process of pancreogenesis is illustrated in Figure 4.
Little cellular ultrastructural differentiation is seen in these early periods of development. During the initial stages of bud elongation the epithelial cells of the pancreas are arranged as simple tubular structures within a loose mesenchymal stroma. From commencement of the fetal period (56 dpc) they become more apparent as branched epithelial clusters. All the different cells types of the pancreas develop from a pool of apparently identical progenitor cells, which are organised in ductal structures in the developing buds.
It is ultimately the regulation and timely expression of gene transcription that provides the mature pancreatic cells with their unique phenotypes-you can’t simply add the different transcription factors and produce a specific cell type. Much research has gone into understanding the hierarchy of transcription factors that regulate the transition from pancreatic progenitor cells to the different cell types found in the adult pancreas. A summary of this process is illustrated in Figure 5 with a description of the different compartments and important transcription factors involved in their differentiation given in Table 1.
Early cells of the pancreas express the transcription factors Pdx1, Ptf1a and Sox9. All the different cell types of the pancreas emerge from these cells. The acinar cells will emerge at the “tips” of the early ductal structures and express Gata4. These cells are highly proliferative and rapidly expand to become the most abundant pancreatic cell type by birth. The ductal lineage emerges from a subset of these early progenitors that lack Pdx1 expression, but continue to express Sox9 into the mature phenotype.
The endocrine portion of the pancreas diverges from these progenitor cells before the onset of hormone expression. A subset of epithelial progenitors positive for Pdx1 and Sox9 give rise to cells that transiently express Ngn3. Ngn3 expression is controlled by the notch signalling pathway. When notch signalling is active the cells do not express Ngn3, it is only in the cells when Notch is inhibited that endocrine differentiation can commence. Without Ngn3 (as investigated in knock-out mice), endocrine differentiation fails and no islets are produced. Ngn3 is therefore necessary to initiate endocrine differentiation, however further factors are required downstream of Ngn3 in order to control the cell specification into one of the 5 different hormone-producing cell types. Pax4, Nkx2.2, Nkx6.1 are co-expressed with Ngn3 and considered “early factors”. Transcription factors downstream of Ngn3 include NeuroD1, Pax6, Isl1 and Pdx1, which is reactivated in the endocrine lineage and has functions in mature β cells.
Insulin is the first hormone to be detected in the developing human pancreas at 52 dpc. Glucagon and somatostatin are identified as separate expression from 60 dpc. The number of hormone-expressing cells increases by 70 dpc, by which time PP can also be detected. The presence of insulin outnumbers that of the other islet hormones throughout development. The islets form relatively early in human development, as compared to the development of mice and rodents where islets are not apparent until within a few days of birth. Endocrine cells in human pancreas development aggregate into large primitive islet structures expressing all the islet hormones by 12-13 weeks post-conception (wpc). Most of the islet cell mass present at birth is due to differentiation from progenitors and not proliferation/replication.
The process of pancreatic organogenesis involves a complex series of interactions and signalling pathways between tissues, cells and their environment. A few of these are summarised below.
o Notochord: Early pancreas development is influenced by the adjacent notochord. The notochord is particularly important for the development of the dorsal pancreas, whilst the ventral pancreas relies more upon interactions from the cardiogenic mesenchyme.
o Mesenchyme: During development the pancreatic epithelium quickly becomes enveloped in pancreatic mesenchyme. Proximity or contact with the mesenchyme is critical for acinar development, whilst endocrine differentiation can only progress in cells where this contact has been lost. When the mesenchyme is absent from cells the “default” programme is differentiation towards islet cells, and in particularly insulin-secreting β cells. When both a basement membrane and mesenchyme are present ductal cells will develop.
o Hedgehog: There are 3 different proteins involved in the hedgehog signalling pathways, Sonic (Shh), Indian (Ihh) and Desert (Dhh). These play vital intercellular signalling roles in embryonic organogenesis and differentiation. The developing gut endoderm expresses the gene coding for the signalling protein Shh and these are essential for the organogenesis of the stomach and duodenum. However, the nearby notochord has Shh-suppressive effects and as a result hedgehog signalling is absent from cells committed to form the pancreas. The hedgehog and notochord signalling therefore provide a molecular boundary beyond which the pancreas cannot form, thereby preventing ectopic pancreas growth.
o Notch Signalling: This is a highly conserved signalling mechanism by which cell-cell interactions occur, it plays a crucial role in embryogenesis. There are well established parallels between development of pancreatic endocrine cells and the nervous system. The notch signalling pathway is normally a regulator of neuronal differentiation, but it also functions in pancreas development. Notch is a cell membrane-bound receptor that, when bound by ligands, maintains cells in an undifferentiated state. This attribute means notch signalling plays a role in growth and expansion of the undifferentiated pancreatic epithelium. Active notch signalling usually prevents endocrine differentiation by inhibiting the expression of Ngn3. When notch signalling is knocked-out in experimental models there is an increase in endocrine differentiation.
o Wnt Signalling: The wnt signalling pathway constitutes a large family of proteins that play a role in cell signalling during development. Several of the genes coding for Wnt factors and receptors have been identified in pancreatic epithelium and mesenchyme, suggesting a role of Wnt signalling in pancreatic development.
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