Interstitial Cajal-Like Cell: A New Player in Cholelithiasis?

Abstract

To the Editor: Th e incidence of gallstones is relatively high in the developed countries, with ~ 10 % of the whole population being aff ected. Even though there is a lack of clear hypothesis on gallstone formation, a few factors are proved to be responsible for this process: cholesterol supersaturation, hydrophobic bile salts, pronucleating proteins, mucus hypersecretion with gel formation in the gallbladder and disrupted gallbladder motility. Th e gallbladder dysmotility seems to be a “ trigger ” event in the pathogenesis of cholesterol gallstones, providing the time necessary for the precipitation of cholesterol microcrystals from bile supersaturated with cholesterol. Considering increasing knowledge of the role of interstitial cells of Cajal in the regulation of gastrointestinal tract (GI) motility as well as in the pathogenesis of multiple GI disorders, and the fact that these cells were recently described in human gallbladder and biliary tract, we wondered whether interstitial cells of Cajal (or interstitial Cajal-like cells — ICLCs — as they are called when localized in extraintestinal organs) are present in gallbladder wall in patients with cholelithiasis and whether their density decreases or perhaps remains intact. We used indirect double immunofl uorescence method to visualize ICLCs. A characteristic feature of ICLCs is the expression of transmembrane tyrosine kinase receptor proteins, including the c-Kit receptor (CD117), which enables the identifi cation of ICLCs. Unfortunately, the CD117 is present in the mast cells as well, and for that reason we stained slides with anti-mast cell tryptase. ICLCs were defi ned as c-Kitpositive nucleated cells that lacked mast cell tryptase expression ( Figure 1 ). ICLCs were observed throughout the gallbladder, including the fundus, body (corpus), and neck, although they were predominantly located in the corpus, almost exclusively within the muscularis propria. ICLCs had a centrally located nucleus and were mostly fusiform in shape; however, sparse, round tryptase / c-Kit-positive cells were also present ( 1 ). In our study (2), we reported for the fi rst time that interstitial Cajal-like cells are lost or damaged in patients suff ering from cholelithiasis. We observed the cells positive for the c-Kit receptor (CD117) in the gallbladder wall in all cases examined. ICLCs were most frequently located in the muscularis propria. Th e density of ICLCs in the muscularis propria was signifi cantly lower in the patients with gallstones than the density observed in the controls (26.24 ± 10.89 vs. 56.29 ± 13.35 cell mm − 2 in the muscularis propria, P < 0.001). Th e published data on ICLCs in the human gallbladder are still very limited. ICLCs were described in the wall of the human gallbladder by Hinescu et al. ( 3 ) and in the bile ducts by Ahmadi et al. ( 4 ). Both teams reported that ICLCs in the gallbladder formed a cellular network that is likely involved in biliary tract motility. Consequently, animal studies suggested the potential role of ICLCs in functional disturbances of the gallbladder. So far, we have not found any works published on ICLCs in the context of pathogenesis of gallstone in humans. Our studies revealed that ICLCs play a role in the pathogenesis of gallstone disease. Furthermore, from the currently fi nished research ( 5 ) we conclude that bile content may infl uence these cells. It implies some possible future medical interventions .