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Epithelial Organization: The Gut and Beyond

Nitesh Shashikanth, Sunil Yeruva, Ma. Lora Drizella M. Ong, Matthew A. Odenwald, Roman Pavlyuk, Jerrold R. Turner

10.1002/cphy.c170003

Source: Volume 7, Issue 4, October 2017

Published online: September 2017

Full Article on Wiley Online Library



ABSTRACT

Epithelial cells are essential to the survival and homeostasis of complex organisms. These cells cover the surfaces of all mucosae, the skin, and other compartmentalized structures essential to physiological function. In addition to maintenance of barriers that separate internal and external compartments, epithelia display a variety of organ‐specific differentiated functions. Function is reflected in overall epithelial structure and organization, shape of individual cells, and proteins expressed by these cells. More than one epithelial cell type is often present within a single organ and, in many cases, individual cells differentiate to change their functional behaviors as part of normal development or in response to extracellular stimuli. This article discusses the diversity of epithelial structure and function in general terms and explores representative tissues in greater depth to highlight organ specific functions and their contributions to physiology and disease. © 2017 American Physiological Society. Compr Physiol 7:1497‐1518, 2017.

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Figure 1. Figure 1. Diversity of epithelial cell shape and function.
Figure 2. Figure 2. Epithelial cell architecture and organization. (A) Fluorescence micrograph of human small intestine labeled for E‐cadherin (green), F‐actin (purple), tight junction protein ZO‐1 (red), and DNA (blue). Note the localization of each protein: actin is present within the cortical actomyosin ring and microvillus brush border, ZO‐1 as bright puncta at tight junctions, and E‐cadherin along basolateral membranes. (B) The apical junctional complex of an intestinal epithelial cell. Tight junction proteins include claudins, zonula occludens 1 (ZO‐1), occludin, and F‐actin, while E‐cadherin, α‐catenin 1, β‐catenin, and F‐actin interact to form the adherens junction. Myosin light chain kinase (MLCK) is associated with the perijunctional actomyosin ring. Desmosomes are formed by interactions between desmoglein and desmocollin, which are bound to keratin filaments. Integrins form focal adhesions with the extracellular matrix proteins. (C) Transmission electron micrograph showing junctional complexes between two enterocytes. The tight junction (TJ) is just below the microvilli (Mv), followed by the adherens junction (AJ). The desmosomes (D) are located basolaterally. (D) Scanning electron micrograph showing microvilli, as viewed from above. (E) Confocal micrograph of cultured small intestinal epithelial cells labeled for F‐actin. In this apical view (from above the cell), microvilli (Mv) can be appreciated as small dot‐like structures due to their F‐actin core. The cortical actin ring that forms a belt around each epithelial cell can also be appreciated at the junction between the two cells shown. (F) Freeze‐fracture electron micrograph showing apical microvilli (Mv) and tight junction strands (TJ) in a cultured intestinal epithelial cell. [Part C from Nature Reviews Immunology (261) and part F from Annual Reviews of Physiology (233) with permission.]
Figure 3. Figure 3. Comparison of small intestinal and colonic mucosal architecture. (A) Low‐magnification image of hematoxylin and eosin‐stained section of normal human duodenum. The mucosa can be separated into villus, crypt, and muscularis mucosae (m. mucosae) and sits atop the submucosa. The villi greatly expand mucosal thickness. (B) Low‐magnification image of hematoxylin and eosin‐stained section of normal human distal colon. The mucosa can be separated into surface, crypt, and muscularis mucosae (m. mucosae) and, like the small intestinal mucosa, rests on the submucosa.
Figure 4. Figure 4. Segregation of epithelial transport proteins along the crypt:villus axis. Fluorescence micrographs of human small intestine labeled for E‐cadherin (red), F‐actin (purple), and DNA (blue). (A) Note the localization of CFTR (green) to the apical membrane of epithelial cells within the lower villus and crypt, the principal site of chloride secretion. (B) Note that NKCC1 (green) is expressed in the same population of cells that expressed CFTR but is localized to the basolateral membrane, where colocalizes with E‐cadherin. (C) NHE3 (green) is localized to the apical membrane and predominantly expressed on cells within the villus, where the bulk of absorption takes place. (D) Similar to NHE3, SGLT1 (green) is localized to the apical membrane of villous absorptive enterocytes. Bright autofluorescence (green) of red blood cells highlights villous capillaries that run just beneath the basement membrane is present in some images (particularly panel C). (E) These transporters are expressed throughout small intestine and colon; similar transporters are expressed within the nephron in a site‐specific manner.
Figure 5. Figure 5. Epithelial glucose transport as a model of Na+‐coupled nutrient absorption. (A) Glucose (Glu) absorption begins with transport across the apical, brush border membrane via SGLT1‐mediated Na+ cotransport. Both glucose and Na+ diffuse to the basolateral membranes where they exit the cell by way of GLUT2 and Na+K+ATPase, respectively. As described in the text, this and the many other Na+ absorptive pathways present can deplete Na+ from the lumen and thereby inhibit further absorption. Tight junction proteins claudin‐2 and claudin‐15 allow Na+ to diffuse, passively, across the tight junction according to the concentration gradient to replenish luminal stores and allow continued nutrient absorption. (B) Fluorescence micrograph of human small intestine labeled for Na+K+ATPase (green), E‐cadherin (red), F‐actin (purple), and DNA (blue). Note the localization of the Na+K+ATPase to the basolateral membranes of villus and crypt epithelial cells. (C) Claudin‐15 (green) is distributed in a dot‐like pattern at epithelial cell junctions. By light microscopy, claudin‐15 appears to colocalize with the very apical extent of E‐cadherin, which is otherwise restricted to the basolateral membrane as well as the dense cortical (perijunctional) F‐actin ring.
Figure 6. Figure 6. Molecular mechanisms of pore and leak pathway regulation by the immune system during disease. (A) IL‐13 results in transcriptional activation of claudin‐2 expression and resulting increases in pore pathway permeability. In contrast, TNF activates myosin light chain kinase transcription and enzymatic activity. These lead to endocytic removal of occludin from the tight junction and increased leak pathway permeability. (B) Transgenic, intestinal epithelial‐restricted expression of constitutively active‐MLCK restores sensitivity of long MLCK−/− mice to adoptive transfer colitis, an immune mediated experimental IBD induced by transfer of CD4+CD45RBhi T cells into Rag1−/− immunodeficient recipients. Long MLCK−/− mice are protected from disease‐associated MLC phosphorylation (green, upper panels) and claudin‐2 upregulation (green, lower panels). Tissue specific, intestinal epithelial expression of a constitutively active MLCK (CA‐MLCK) catalytic domain restores disease‐associated MLC phosphorylation and claudin‐2 upregulation. Thus, although inflammatory cytokines can specifically and differentially activate pore and leak pathways, the regulation of these paracellular flux routes is linked in disease. Bar = 10 um. [Part B adapted from Gastroenterology (245) with permission.]


Figure 1. Diversity of epithelial cell shape and function.


Figure 2. Epithelial cell architecture and organization. (A) Fluorescence micrograph of human small intestine labeled for E‐cadherin (green), F‐actin (purple), tight junction protein ZO‐1 (red), and DNA (blue). Note the localization of each protein: actin is present within the cortical actomyosin ring and microvillus brush border, ZO‐1 as bright puncta at tight junctions, and E‐cadherin along basolateral membranes. (B) The apical junctional complex of an intestinal epithelial cell. Tight junction proteins include claudins, zonula occludens 1 (ZO‐1), occludin, and F‐actin, while E‐cadherin, α‐catenin 1, β‐catenin, and F‐actin interact to form the adherens junction. Myosin light chain kinase (MLCK) is associated with the perijunctional actomyosin ring. Desmosomes are formed by interactions between desmoglein and desmocollin, which are bound to keratin filaments. Integrins form focal adhesions with the extracellular matrix proteins. (C) Transmission electron micrograph showing junctional complexes between two enterocytes. The tight junction (TJ) is just below the microvilli (Mv), followed by the adherens junction (AJ). The desmosomes (D) are located basolaterally. (D) Scanning electron micrograph showing microvilli, as viewed from above. (E) Confocal micrograph of cultured small intestinal epithelial cells labeled for F‐actin. In this apical view (from above the cell), microvilli (Mv) can be appreciated as small dot‐like structures due to their F‐actin core. The cortical actin ring that forms a belt around each epithelial cell can also be appreciated at the junction between the two cells shown. (F) Freeze‐fracture electron micrograph showing apical microvilli (Mv) and tight junction strands (TJ) in a cultured intestinal epithelial cell. [Part C from Nature Reviews Immunology (261) and part F from Annual Reviews of Physiology (233) with permission.]


Figure 3. Comparison of small intestinal and colonic mucosal architecture. (A) Low‐magnification image of hematoxylin and eosin‐stained section of normal human duodenum. The mucosa can be separated into villus, crypt, and muscularis mucosae (m. mucosae) and sits atop the submucosa. The villi greatly expand mucosal thickness. (B) Low‐magnification image of hematoxylin and eosin‐stained section of normal human distal colon. The mucosa can be separated into surface, crypt, and muscularis mucosae (m. mucosae) and, like the small intestinal mucosa, rests on the submucosa.


Figure 4. Segregation of epithelial transport proteins along the crypt:villus axis. Fluorescence micrographs of human small intestine labeled for E‐cadherin (red), F‐actin (purple), and DNA (blue). (A) Note the localization of CFTR (green) to the apical membrane of epithelial cells within the lower villus and crypt, the principal site of chloride secretion. (B) Note that NKCC1 (green) is expressed in the same population of cells that expressed CFTR but is localized to the basolateral membrane, where colocalizes with E‐cadherin. (C) NHE3 (green) is localized to the apical membrane and predominantly expressed on cells within the villus, where the bulk of absorption takes place. (D) Similar to NHE3, SGLT1 (green) is localized to the apical membrane of villous absorptive enterocytes. Bright autofluorescence (green) of red blood cells highlights villous capillaries that run just beneath the basement membrane is present in some images (particularly panel C). (E) These transporters are expressed throughout small intestine and colon; similar transporters are expressed within the nephron in a site‐specific manner.


Figure 5. Epithelial glucose transport as a model of Na+‐coupled nutrient absorption. (A) Glucose (Glu) absorption begins with transport across the apical, brush border membrane via SGLT1‐mediated Na+ cotransport. Both glucose and Na+ diffuse to the basolateral membranes where they exit the cell by way of GLUT2 and Na+K+ATPase, respectively. As described in the text, this and the many other Na+ absorptive pathways present can deplete Na+ from the lumen and thereby inhibit further absorption. Tight junction proteins claudin‐2 and claudin‐15 allow Na+ to diffuse, passively, across the tight junction according to the concentration gradient to replenish luminal stores and allow continued nutrient absorption. (B) Fluorescence micrograph of human small intestine labeled for Na+K+ATPase (green), E‐cadherin (red), F‐actin (purple), and DNA (blue). Note the localization of the Na+K+ATPase to the basolateral membranes of villus and crypt epithelial cells. (C) Claudin‐15 (green) is distributed in a dot‐like pattern at epithelial cell junctions. By light microscopy, claudin‐15 appears to colocalize with the very apical extent of E‐cadherin, which is otherwise restricted to the basolateral membrane as well as the dense cortical (perijunctional) F‐actin ring.


Figure 6. Molecular mechanisms of pore and leak pathway regulation by the immune system during disease. (A) IL‐13 results in transcriptional activation of claudin‐2 expression and resulting increases in pore pathway permeability. In contrast, TNF activates myosin light chain kinase transcription and enzymatic activity. These lead to endocytic removal of occludin from the tight junction and increased leak pathway permeability. (B) Transgenic, intestinal epithelial‐restricted expression of constitutively active‐MLCK restores sensitivity of long MLCK−/− mice to adoptive transfer colitis, an immune mediated experimental IBD induced by transfer of CD4+CD45RBhi T cells into Rag1−/− immunodeficient recipients. Long MLCK−/− mice are protected from disease‐associated MLC phosphorylation (green, upper panels) and claudin‐2 upregulation (green, lower panels). Tissue specific, intestinal epithelial expression of a constitutively active MLCK (CA‐MLCK) catalytic domain restores disease‐associated MLC phosphorylation and claudin‐2 upregulation. Thus, although inflammatory cytokines can specifically and differentially activate pore and leak pathways, the regulation of these paracellular flux routes is linked in disease. Bar = 10 um. [Part B adapted from Gastroenterology (245) with permission.]
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Teaching Material

N. Shashikanth, S. Yeruva, M. L. D. M. Ong, M. A. Odenwald, R. Pavlyuk, J. R. Turner. Epithelial Organization: The Gut and Beyond. Compr Physiol 7: 2017, 1497-1518. doi:10.1002/cphy.c170003

Didactic Synopsis

Major Teaching Points:

  • Epithelial cells work in unison to form barriers that are necessary for separating self from non-self and preventing mixing of distinct compartments within complex organisms.
  • Epithelial structure and organization varies widely and reflects the specialized functions of the sites in which they are found.
  • Core functions common to most epithelia include protection, sensation, transport, secretion, clearance, and repair.
  • Polarization of epithelial cell structures, including development of distinct plasma membrane domains, targeted protein localization, and cytoskeletal organization is essential to epithelial function.
  • Coordinated activity of transmembrane transport proteins as well as flux across the paracellular pathway, i.e. the tight junction, is required for vectorial transport.
  • Disorders of epithelial function can cause and contribute to disease.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1. Diversity of epithelial cell shape and function. This figure demonstrates the diversity of epithelial cell shape and function at representative sites.

Figure 2. Epithelial cell architecture and organization. This figure depicts the organization of an epithelium. The cartoon in the middle is representative of what occurs when two epithelial cells adhere. Readers can appreciate organization of the junction complexes and the microvilli, from different cross sectional planes as mentioned. A zoomed in electron micrograph of microvilli shows the view from atop an intestinal epithelial cell. [Part C from Nature Reviews Immunology and part F from Annual Reviews of Physiology, with permission.]

Figure 3. Comparison of small intestinal and colonic mucosal architecture. This figure highlights regional specializations within a single organ system, that is, the gastrointestinal tract. It compares the features of the small intestine and the colon.

Figure 4. Segregation of epithelial transport proteins along the crypt:villus axis. This figure shows differential expression of transport proteins during epithelial differentiation as well as polarity of trafficking. Sketches of the intestine and kidney nephron show that sites of expression and transporters expressed differ within and across organs.

Figure 5. Epithelial glucose transport as a model of Na+-coupled nutrient absorption. This figure describes the complex interplay between apical transmembrane transport proteins, basolateral transmembrane transport proteins, and the paracellular path across the tight junction during Na+-coupled nutrient absorption. Accompanying photomicrographs demonstrate the localization of related proteins.

Figure 6. Molecular mechanisms of pore and leak pathway regulation by the immune system during disease. This figure illustrates distinct mechanisms of tight junction regulation by inflammatory cytokines. Photomicrographs from mice with experimental disease are used to demonstrate the relationship between these mechanisms. [Part B adapted from Gastroenterology journal, with permission.]


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Article Title: Epithelial Organization: The Gut and Beyond
 

How to Cite

Nitesh Shashikanth, Sunil Yeruva, Ma. Lora Drizella M. Ong, Matthew A. Odenwald, Roman Pavlyuk, Jerrold R. Turner. Epithelial Organization: The Gut and Beyond. Compr Physiol 2017, 7: 1497-1518. doi: 10.1002/cphy.c170003