**2.1 Hepatic stellate cells**

 Vitamin A is mostly (≈80%) stored in hepatic stellate cells, which are located in the perisinusoidal (Disse) space [1, 2]. Lipid droplets containing vitamin A can be assessed by electron microscopy. Vitamin A-rich (containing ≥10 vitamin A lipid droplets) (**Figure 1A**) and vitamin A-poor stellate cells (<10 vitamin A lipid droplets) can be identifed by counting the numbers of lipid droplets in the cytoplasm. In humans and experimental animals, vitamin A-rich stellate cells change to vitamin A-poor stellate cells or myofbroblasts, which induce fbrosis by collagen formation in chronic hepatitis or cirrhosis (**Figure 1B**).

Portal fbrosis is induced by collagen produced mainly by stellate cells but not by hepatocytes. Collagen-producing stellate cells change into myofbroblast-like cells, which show a decrease in the number of vitamin A granules in the cytoplasm, and produce collagen around the cytoplasm. Lastly, vitamin A granules disappear completely from the cytoplasm, and stellate cells change their phenotype to that of myofbroblasts and fbrocytes, which are immunohistochemically positive for anti-αSM-actin antibody [12–14].

 Te periportal area is a microenvironment with a high concentration of vitamin A due to an abundance of vitamin A-rich stellate cells, and the complex of retinolretinol binding protein is paracrine-transferred from hepatic parenchymal cells to stellate cells, leading to direct secretion of the complex from stellate cells into the plasma [15–17]. Since hepatic stem cells are localized around the periportal area, namely the canal of Hering, the diferentiation and maturation of these cells may be impaired due to vitamin A depletion in this area [18–20]. Hepatic stellate cells require vitamin A-rich lipids to maintain their niche function. Accordingly, the hepatic stem cell-stem cell niche relation is maintained in the periportal area [21, 22] (**Figure 2A**).

#### **Figure 1.**

*(A) A periportal vitamin A-rich stellate cell containing many lipid droplets and exerting pressure on the nucleus (human liver). (B) A periportal vitamin A-poor stellate cell containing a few lipid droplets (arrow) and well-developed endoplasmic reticulum (human liver).* 

*The Role of Vitamin A-Storing Cells (Stellate Cells) in Inflammation and Tumorigenesis DOI: http://dx.doi.org/10.5772/intechopen.83523* 

### **2.2 Subepithelial myofbroblasts as colonic stellate cells**

 In the colonic mucosa, subepithelial myofbroblasts correspond to hepatic stellate cells, although they are usually vitamin A-poor in the cytoplasm, suggesting a diferent endotype from hepatic stellate cells (**Figure 3**). Subepithelial myofbroblasts are localized more at the crypt base than at other regions (**Figure 2B**) [3]. Subepithelial myofbroblasts express αSM-actin, NCAM, cytoglobin, and HSP47, indicating multipotential roles [3, 11, 23] (**Figure 4**). Because stem cells are localized at the crypt base, subepithelial myofbroblasts around the crypt base are considered a stem cell niche, which has been shown by experimental and histopathological studies [3, 5, 23–25]. Accordingly, mucosal stem cells require subepithelial myofbroblasts for their diferentiation. Critical gene expression paterns were shown from the colon basal crypts to the colon tops, including bone morphologic protein (BMP) antagonists, gremlin 1 (*GREM1*)*, GREM2, CHRDL1*, and active Wnt signaling using human colon microarray analysis [5]. Along the colon crypt axis, Wnt signaling and Notch signaling expression were activated at the crypt base, while BMP signaling was activated at the top. Wnt signaling and Notch signaling by subepithelial myofbroblasts of the crypt base and smooth muscle cells of the muscularis mucosa regulate epithelial cell positioning and proliferation, and BMP induces epithelial diferentiation. Further, isolated human colonic crypt epithelial cells expressing musashi-1, β1-integrin, BerEP4, and CD133 have been shown to adhere to colonic myofbroblasts in cell incubation experiments, indicating an intimate interaction with each [26, 27].

#### **Figure 2.**

*(A) Characteristic distribution of periportal vitamin A-rich stellate cells in the liver. Hepatic stem cells located in zone 2, where vitamin A-rich stellate cells are collected, form a stem cell niche. Periportal hepatic cells differentiate and maturate toward zone 5, close to the centrilobular vein [22]. (B) Localization and distribution of subepithelial myofibroblasts in the colonic mucosa. Many subepithelial myofibroblasts can be seen around the crypt base forming a stem cell niche, where colonic stem cells are located. Epithelial cells at the crypt base differentiate and maturate toward the crypt top [3, 11]. The characteristic localization and maintenance of stem cell-stem cell niche are similar to those of the hepatic lobule. MM: Muscularis mucosa.* 

#### **Figure 3.**

*(A) Localization of subepithelial myofibroblasts in human colonic mucosa. Many subepithelial myofibroblasts, vitamin A-absent (a) or vitamin A-poor (b), are located around the crypt base. An interstitial myofibroblast is also seen (c). (B) A vitamin A-poor (arrow) subepithelial myofibroblast adjacent to the crypt.* 

#### **Figure 4.**

*Expression of αSM-actin and NCAM by subepithelial myofibroblasts in human colonic mucosa. Double immunofluorescence staining shows expression of both αSM-actin (red arrows) and NCAM (green arrows).* 

Tus, the localization and relation of the stem cell-stem cell niche is the same in the liver and intestine.
