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Rao JN, Wang JY. Regulation of Gastrointestinal Mucosal Growth. San Rafael (CA): Morgan & Claypool Life Sciences; 2010.

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Regulation of Gastrointestinal Mucosal Growth.

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Intestinal Architecture and Development

The architecture of GI tract and its developmental features of different segments have been well defined. Several excellent review articles in this area are readily available [15]. Here, we only provide a brief overview on GI architecture and its developmental aspects that are relevant to our understanding of GI mucosal growth and regulation.


The primary functions of GI tract include digestion and absorption of nutrients, secretions, and immunoresponse. The unique architecture of the GI tract facilitates these functions, including multiple levels of infolding that result in an immense surface area, thus allowing maximal nutrient absorption. The wall of the intestine is conventionally described in terms of its component layers, and these layers are not separated entirely from one another but are joined together by connective tissue and by the neural and vascular elements. All segments of the GI tract are divided into four layers: the mucosa (epithelium, lamina propria, and muscular mucosae), the submucosa, the muscularis propria (inner circular muscle layer, intermuscular space, and outer longitudinal muscle layer), and the serosa (Figure 1). Mucosa is the innermost layer, which is structurally and functionally the most complex and important area. The mucosal surfaces of the body are the areas where important absorptive function occurs. The mucosa consists of three layers. The first layer facing the intestinal lumen is made up of epithelial cells, which is a single layer in the GI tract and is attached to a basement membrane overlying the second layer, the lamina propria, which consists of subepithelial connective tissue and lymph nodes, underneath which is the third and deepest layer called muscularis mucosae. This is a continuous sheet of smooth muscle cells that lies at the base of the lamina propria. The entire mucosa rests on the submucosa, beneath which is the muscularis propria. The outermost layer is named as the serosa or, if it lacks an outer layer of mesothelial cells, the adventitia. The submucosa consists of a variety of inflammatory cells, lymphatics, autonomic nerve fibers, and ganglion cells. This area is also a branching and distribution zone for arteries and small venous channels.

FIGURE 1. Architecture of the gut mucosal wall.


Architecture of the gut mucosal wall. Four-layered (mucosa, submucosa, muscularis mucosa, and serosa) organization of the digestive tract. Adapted from (permission pending).

In the GI tract, the muscularis propria contains smooth muscle cells organized into a tightly coiled, inner circular layer and outer longitudinal layer, as shown in Figure 1. The smooth muscle cells are arranged in parallel arrays. Between the outer and inner layers of the muscularis propria are prominent autonomic neural fibers and ganglionic clusters that form a myenteric plexus. The major functions of the muscularis propria are to propel food through the gut by contractile peristaltic waves initiated and regulated by various neural and hormonal events [2,6]. Flow is regulated by peristaltic mechanisms and by sphincters located in the upper esophagus, in the distal portions of the esophagus, stomach, and ileum and in the anus. Most part of the intestine is lined on its outer surface by a sheath of protective layer, the serosa, which consists of a continuous sheet of squamous epithelial cells, the mesothelium, separated from the underlying longitudinal muscle layer by a thin layer of loose connective tissue (Figure 1). The serosal layer forms a natural barrier from the spread of inflammatory and malignant processes [7,8].


The development of the mammalian GI system is preprogrammed, but this can be altered during the intrauterine and early postnatal life [6,9,10]. There are two major steps involved in the development of the GI tract, formation of the gut tube and formation of the individual organs with their specialized cell types. Genes regulating both phases are being identified and well characterized in published comprehensive reviews [6,11,12].


The esophagus is the foremost part of the GI tract that can be identified as a distinct structure early in the human embryogenesis. This organ elongates during subsequent development relatively more rapidly than the fetus as a whole [2,6,13]. The major events during the formation of esophagus are as follows: at 10 weeks, ciliated columnar epithelium appears followed by the replacement of stratified squamous epithelium at around 20–25 weeks, a process that begins in the mid-esophagus and proceeds further [14]. Studies by Hitchcock et al. [9] show the development of esophageal musculature and innervation in fetuses at 8–20 weeks of gestation and in infants at 22–161 weeks of age. The esophagus is well supplied with lymphatics that form a richly anastomosing network in the lamina propria and submucosa. Although the esophagus is described as a tube, it is oval and has a flat axis anterior to posterior with a wider transverse axis. The primary functions of the normal esophagus are the propulsion of food from the mouth to the stomach and the prevention of significant reflux of gastric contents into the esophagus. The propulsive function is affected by involuntary peristalsis in the muscularis propria that unlike the remainder of the GI tract is formed by two types of muscle fibers, such as striated and smooth muscles [2,15]. When it is on the resting state, the esophagus is a collapsed tube, and the elastic tissue in its walls accounts for its distensability. During swallowing, the lumen dilates, and the folds flatten so that the esophagus can normally accommodate the passage of even large amounts of food bolus.


The stomach receives food from esophagus and is a J-shaped reservoir of the digestive tract, in which ingested food is soaked in gastric juice that contains digestive enzymes acids [2,12]. The prenatal ultrasound examinations have revealed that the stomach grows in a linear fashion from 13 to 39 weeks and that the characteristic anatomic features, such as greater curvature, fundus, body, and pylorus, are identified in as early as 14 weeks [6]. The stomach is located in the left upper quadrant of the abdomen, and its upper portion lies beneath the dome of the left hemi-diaphragm. The stomach is divided into four zones, each of which has a specific microscopic mucosal structure. The “cardia” is the narrow portion of the stomach immediately distal to the gastroesophageal junction. The remainder of the stomach is divided into proximal and distal parts. The proximal portion is the body or corpus, and the distal part is named as pyloric antrum which is demarcated from the duodenum by the pyloric sphincter. The pyloric sphincter is closed in the resting state to prevent the reflux of intestinal contents into the stomach (Figure 2). The arterial blood supply to the stomach involves many different branches, among which, splenic artery, common hepatic, and left gastric arteries are important. Venous drainage from the stomach is through the portal system to the liver. Deeper in the epithelial wall is a rich lymphatic network that drains to the regional perigastric lymph nodes and to the nodes in the omentum, around the head of the pancreas and in the spleen [16]. In the stomach, solid food is fragmented and mixed by peristalsis. A semiliquid material (chime) is formed and released in small, regulated bursts into the duodenum by rhythmic openings of the pyloric sphincter. Cells in the corpus and fundus of the stomach also produce hydrochloric acid and intrinsic factors necessary for absorption. Although it occurs predominantly in the small intestine, some digestion occurs in the stomach. Certain gastric mucosal cells produce pepsinogens, the proteolytic enzymes that are secreted in an inactive form, but they are then activated by the acid environment of the gastric lumen during food intake. In addition, production of the hormone gastrin is also another major gastric function. The development of gastric glands (fundic type or oxyntic) occurs very early during human fetal life (10–12 weeks of gestation) [6,17,18]. The advance and detailed description of development, gastric endocrine cells, and functions of the stomach are described in recent review articles [6,13,19].

FIGURE 2. Architecture of human digestive system. Adapted from (permission pending).


Architecture of human digestive system. Adapted from (permission pending).

Small Intestine

The intestinal tract followed by the stomach consists of the small intestine, including duodenum, jejunum, and ileum, and the large intestine or colon (Figure 2). The development of small intestine consists of three successive phases: morphogenesis and cell proliferation, cell differentiation, and cellular and functional maturation [6,20]. Organogenesis of the intestine is completed by 13 weeks of gestational period [21]. The duodenum is the first portion of the small intestine and extends approximately 25 to 30 cm from the pyloric sphincter to a fibrous and muscular band, the ligament of Treitz. From the distal part of the stomach, duodenum enters the retroperitoneum, curves, and then enters into peritoneal cavity. Jejunum and ileum are located between the Trietz and the ileocecal sphincter. First one-third of this segment of the small intestine is referred as the jejunum, whereas the remainder is named as the ileum. Structure and function of jejunum and ileum are different and occur gradually during the development. The blood supply for the three segments of small intestine derives from the celiac, superior, and inferior mesenteric arteries, respectively. The cecal and appendiceal diverticulum appear during 6 weeks of gestation, marking the margin between the small and large intestines. The inner surface of the small intestine is covered with a simple columnar epithelium exhibiting invaginations, known as the crypts of Lieberkuhn, which are comprised predominantly of proliferating cells, and finger-like projections called villi that contain the majority of differentiated absorptive cells [2,6,19]. The epithelial lining initiates and modulates the basic activities attributed to the small intestine, like terminal digestion of nutrients and transport of nutrients, water, and ions. The epithelial surface is expanded by villous thickness and crypts present between villi. The adult small intestinal epithelium is composed of four different cell lineages. Differentiated cells, such as enterocytes, enteroendocrine, and goblet cells, occupy the villi, while another type of differentiated cells, the Paneth cells, reside at the bottom of the crypts and secrete antimicrobial agents. The remaining part of the crypts constitutes the stem cells and proliferating progenitor compartment [20,21].

Large Intestine

The large intestine or the colon arches around the small intestine, commencing in the right ileac region. In adult humans, the colon is approximately 1.5 m in length. The parts of the large intestinal anatomic divisions from proximal to distal end include the cecum, ascending colon, hepatic flexure, transverse colon, splenic flexure, descending colon, sigmoid colon, rectum, and anus. The structure of the colon in many respects overlaps that of the small intestine as described previously [2,6,22]. Development of the colon is marked by three important cytodifferentiative stages, which include the appearance of primitive stratified epithelium to a villous architecture with developing crypts at about 12–14 weeks of gestation and followed by the remodeling of the epithelium at around 30 weeks when the villi disappear and the adult-type crypt epithelium is established [6]. Concurrent with the presence of villous morphology, the colonic epithelial cells express differentiation markers similar to those in small intestinal enterocytes [22]. As seen in the small intestine, lymphoid nodules that distort the normal mucosal architecture are present in the colon, and the colonic epithelium also rapidly renews by itself. Undifferentiated crypt cells appear to be the progenitor for all cell types in the colon. In contrast to the small intestine, the mucosa of the large intestine is not covered with villous projections but it contains deep tubular pits that increase in depth toward the rectum and extends as far as the muscularis mucosa. Colonic mucosal epithelial cells include absorptive cells, goblet mucus cells, undifferentiated columnar crypt cells, caveolated cells, Paneth cells, and M-cells present in the colonic mucosa and are almost identical to those cells present in the small intestine. The major functions of the colon are to reclaim luminal water and electrolytes.

Copyright © 2011 by Morgan & Claypool Life Sciences.
Bookshelf ID: NBK54098


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