203Comparative Anatomy and Histology.© 2012 Elsevier Inc. All rights reserved.2012

Suzanne M. Dintzis and Denny Liggitt University of Washington School of Medicine, Seattle, WA, USA

Gross AnatomyThe pancreas is a large, relatively flat, white-to-pink-colored organ that develops from an outgrowth of the primitive foregut. It is a combined endocrine and exocrine gland in close association with the upper duodenum. During development, exocrine and endocrine elements are both derived from differentiation of duct epithelium. Depending on the species, the gross anatomical pattern of the pancreas presents as either a “mesenteric” or a “compact” type (Figures 1 and 2). As implied by the name, the mesenteric pattern describes the pancreas’ relatively diffuse dispersion within the duodenal mesentery. In this pattern, lobules and segments are separated, sometimes widely, by mesenteric fat and stromal elements including lymphoid aggregates in mice. This dispersion of pancreatic elements makes it difficult to accurately weigh a mesenteric pancreas. The mesenteric pattern is present in the rabbit and in the mouse and rat in a slightly more compacted form. In the typical compact presentation—which occurs in human, monkey, dog, and hamster—the organ is denser and more closely confined within the curve of the upper duodenum. In contrast to the mesenteric type, this compact presentation permits distinct regions of the pancreas to be recognized more readily by the gross anatomic terms head, neck, body, and tail.

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HistologyPancreata from humans and mice share many histological and functional similarities but also display some potentially important differences (Table 1). The pancreas is invested by a very thin connective tissue capsule (Figures 3 and 4) and divided into lobules, which in turn are formed from dense accumulations of exocrine glands that often surround islets of Langerhans. Individual lobules are defined by the thin connective tissue capsule extending into the parenchyma in the form of septa. These septa and associated interlobular connective tissues support blood and lymph vessels, nerves, ganglia, and pancreatic ducts. Arteries that supply the pancreas divide into arterioles within this space and distribute to individual lobules. Lymphatics are not obvious in normal histologic preparations, and species differences have not been described. The size of lobules is roughly relative to the size of the species; hence, lobules are small in mice and larger in humans. A similar size association does not exist with islets.

The exocrine portion of the pancreas is formed from tightly packed clusters of branched, interdigitating compound tubuloacinar glands that are aggregated into lobules. Large pyramidal secretory epithelial cells that surround and define

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a lumen are grouped into acini. The luminal orientation of acini will only occasionally be clearly recognizable (Figure 5) due to the two-dimensional nature of histologic sections and the complexity of the acinar architecture. At the luminal surface, acinar cells are attached by apical tight junctions, and at the basal surface they are supported by a basal lamina. The acinar cells have a basal to centrobasal nucleus, and in rodents these cells may have two nuclei. Acinar cells have prominent endoplasmic reticulua and Golgi complexes, and their cytoplasm may contain large quantities of secretory (zymogen) granules clustered toward the apical surface of the cell. These refractile granules stain intensely red with H&E. The zymogen granules contain a variety of digestive enzymes, most of which become activated upon entry into the duodenum. Although acinar

FIGURE 1 Mesenteric pancreas from adult mouse. Lobes and lobules are dispersed and separated by mesenteric fat, connective tissue, and lymphoid aggregates (arrow).

FIGURE 2 Compact type of pancreas from human. The pancreas structure is more dense in humans. Individual or small clusters of adipocytes are present as small clear foci. These can be seen in older or obese mice and humans.

FIGURE 3 Mesenteric type of pancreas from mouse. A thin fibrous capsule invests the pancreas of this young adult mouse and extends into the parenchyma to divide it into lobes and lobules (arrow). The intralobular stroma supports blood vessels, lymphatics, and nerves.

Feature Mouse Human

Gross Gross anatomic pattern Mesenteric Compact

Tissue Lobule size Small LargeIslet size (diameter) 116 80 μm 50 29 μmIslet location Unevenly distributed through organ; most

interlobularEvenly distributed through organ; most intralobular

Cells Islet cells Beta cells predominate (75%), alpha cells lower (18%); beta cells central, alpha and gamma cells peripheral

Beta cells less dominate (55%), alpha cells higher (37%); islet cells scattered and randomly distributed along vessels

Pancreatic ducts Primary duct joins bile duct prior to entry into duodenum; multiple accessory ducts are common

Primary duct joins bile duct at greater duodenal papillae; single accessory duct is common

Microvasculature Insuloacinar portal system and insulovenous efferent systems are present; in islets, basal lamina accompanies vessels only

Insuloacinar portal system dominates; in islets, basal lamina accompanies endocrine cells and vessels (“double” basement membrane)

TABLE 1 Pancreas

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cells from humans and mice appear histologically similar and relatively uniform, they are actually composed of a rather heterogeneous population. For instance, acinar cells in close proximity to islets tend to be larger and to contain more digestive enzymes compared to more distant ones. Other functional and structural markers confirm acinar cell heterogeneity, but clear species differences remain to be described.

The large zymogen granule-rich epithelial cells lining the acinar glands merge at the luminal surface with relatively clear-staining flattened oval-to-cuboidal centroacinar cells, which may

FIGURE 4 The human pancreas. The interlobular stroma and capsule are more prominent in the pancreas from an older human.

l Need-to-known Mouse pancreas is loosely dispersed in a “mesenteric”

pattern, whereas the human pancreas has a “compact” presentation with distinct head, neck, body, and tail regions.

n The pancreatic capsule extends to divide the parenchyma of both species into lobes and lobules. This capsule is typically thin but can thicken with age.

d

FIGURE 5 Zymogen granule-rich acinar epithelial cells from an adult mouse. Vascular and intercalated ductal (d) elements are also present. In rodents, multinucleated acinar cells can be observed (arrows).

be somewhat indistinct in normal pancreas from a young adult mouse (Figure 6). Centroacinar cells are continuous with the lumen of the intercalated duct. The progression of excretory ducts from smallest to largest is intercalated→intralobular→interlobular→main pancreatic duct. As ducts increase in size, their lining changes from cuboidal to low columnar to columnar epithelium, the lining of the main pancreatic duct. Ductal epithelial cells may have cilia or microvilli, and goblet cells are also occasionally present in main pancreatic ducts. In humans, the main pancreatic duct enters the duodenum at the greater duodenal papilla (papilla of Vater) along with the common bile duct. Most people have a small accessory duct that opens into the proximal duodenum. In mice, pancreatic exocrine secretions typically drain into the duodenum via the common bile duct. Multiple accessory ducts, such as those associated with the dispersed mesenteric lobules, may also be present and drain directly into the duodenum. Interestingly, pancreatic ductal cells remain pluripotent and can give rise to both acinar and islet cells following some types of pancreatic injury.

The endocrine portion of the pancreas is represented by islets of Langerhans, which account for 1 or 2% of pancreas volume (lower in mice than in humans). Islets vary in size, location, and composition within and between species. The average mouse islet is approximately twice the diameter of a human islet, but sizes in both species (particularly in mice) are widely

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distributed and may overlap. Exceptionally large islets can occasionally be seen in humans as well as in pregnant or obese mice (Figures 7 and 8). In mice, islets tend to be unevenly distributed throughout the pancreas. As such, it is possible to view sections that lack islets. An additional important difference is that in mice, as well as in rats and guinea pigs, islets are present in both interlobular/periductal and, occasionally, intralobular locations (Figures 9 and 10). Many pancreatic lobules in mice in particular lack islets. This contrasts with humans—as well as monkeys, cows, pigs, dogs, rabbits, and cats—in whom islets are mostly intralobular.

Human and rodent islets are composed of various combinations of the three primary endocrine cell types and supporting stromal elements: alpha cells, which secrete glucagon; beta cells, which secrete insulin and amylin; and gamma cells, which secrete somatostatin. Also present in much lower numbers are several additional subtypes of islet cells and mediators, including epsilon cells, which secrete ghrelin, and PP or F cells, which

(A) (B)

FIGURE 6 Centroacinar cells from mouse and human. Centroacinar cells (arrows) in a normal young adult mouse (A) areless distinct than those in the pancreas from an older adult human (B).

FIGURE 7 Example of a large interlobular islet from an adult mouse. A corona of enlarged acinar cells surrounds this islet.

secrete pancreatic polypeptide. Species differences in islet cells are not obvious in H&E-stained sections (Figure 11). Accurate identification of islet cell types and distributions depends on the use of appropriate immunohistochemical or other

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special staining techniques. The composition and distribution of endocrine cells within individual islets vary greatly between and within species and with the physiologic state; however, some basic differences exist. For instance, in primates (including humans), the frequency of islets containing a mixture of endocrine cell types is higher, and fewer of these cells overall are beta cells compared to those in mice, in which islets composed primarily of beta cells predominate. In addition, in normal mice, these dominant beta cell populations are typically clustered in the center of the islet and surrounded by other islet

FIGURE 8 Section of pancreas from an older human showing three intralobular islets. Note the normal variation in islet size, with the two small islets being more typical. Clear foci are adipocytes.

l Need-to-known Acinar structure in humans and mice is similar,

although mouse acinar cells may be multinucleated. In mice, the primary pancreatic duct joins the bile duct prior to emptying into the duodenum, and multiple accessory ducts are common. In humans, the primary pancreatic duct joins the bile duct at the greater duodenal papillae, and only a single accessory duct is common.

n Islets vary greatly in size, particularly in mice. Islets tend to be distributed unevenly throughout the mouse pancreas, in contrast to the more even distribution in the human pancreas.

FIGURE 9 Mouse islets. As shown here, most islets in the mouse are located in interlobular spaces and are often periductal or perivascular. In this figure, the interlobular duct contains pink secretory material, and the artery is filled with red blood cells.

FIGURE 10 Human islets. In the human, islets are principally found in intralobular locations, lack a close association with larger ducts and vessels, and are closely surrounded by acinar cells.

cell types, whereas in humans the various islet cell populations are intermingled and closely, but randomly, associated with islet blood vessels.

Understanding of pancreatic microvascular anatomy in general and of islets in particular remains incomplete. Islets are highly vascularized and have sinusoidal capillaries with similarities to renal glomeruli. Capillaries that serve the islets are 5 times denser and have approximately 10 times more fenestrations than those serving the exocrine pancreas. In humans, both islet cells and islet vessels have basal lamina, resulting in

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a “double” basement membrane. In mice, only a single basement membrane is present, and it accompanies blood vessels. The manner in which blood flows through an islet may have significant functional consequences, and several blood flow models have been proposed and continue to be refined. Despite differences, each of these models accounts for the concept of an insuloacinar portal system whereby blood that passes through an islet then perfuses acinar tissue (Figure 12). Functionally, this may account for the presence of relatively larger acinar cells, which can be seen to surround some islets (Figure 7). Species differences that do exist are to some degree related to the predominance of interlobular islets compared to intralobular islets as well as to distribution of cell types within islets, islet size, and other variables. In mice, in which the vast majority of islets are interlobular, the islets are supplied by lobular vessels that drain into the insuloacinar portal system as well as directly into lobular veins (insulovenous efferent system). This contrasts with humans, in whom most islets are intralobular, and in whom the insuloacinar portal system dominates. Although species differences in pancreatic circulation are recognized, none are absolute; they can vary based on islet size, metabolic state,

D(A) (B)

FIGURE 11 Comparison of islets from an older human (A) and younger mouse (B). Stromal elements are more prominent in the human islet, which is a reflection of age rather than a fundamental histologic difference. Also note the pancreatic duct (D) in close proximity to the islet of the mouse, which is typical for this species. Comparing islet cell composition between the species requires special stains or immunohistochemical methods to differentiate cells.

l Need-to-known In mice, islets are mostly interlobular; human islets are most commonly intralobular. Many lobules in mice lack any islets.

n With immunohistochemistry, it can be seen that in mice, beta cells predominate and tend to be more centrally located than in humans, in whom beta cells are less dominant and more randomly distributed.

Pancreatic acini

Acinar vascular

system

Islet of

Langerhans

5

4Insuloacinar

portal system

FIGURE 12 Blood supplying islets continues on to supply acini via the insulo-acinar portal system. In addition, acini may be supplied directly via an independent arterial-venous system. In mice, because many islets are interlobular, blood emanating from these islets may flow directly into veins without passing through acinar tissues. Source: Reprinted from Histology and Cell Biology, 2e, Kierszenbaum, A.L. www.netterimages.com 2007, with permission from Mosby, © Elsevier.

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F U R T H E R R E A D I N G

association (or lack thereof) with lobular tissue, and location within the pancreas.

Because of ease of access to tissues, a great deal of what is known about the normal pancreas has been derived from experimental animals, particularly young normal rodents. This presents a challenge in that comparisons are typically made with human autopsy tissue that is often from older, medically compromised individuals.

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In addition, throughout the years, investigations of pancreatic structure and function involving different species have naturally merged into hybrid models or prototypes. It is important to consider known and emerging differences when making translations between species because it is increasingly obvious that although there are great similarities, dependence on either structural or functional prototypes may not always be reliable.