Changes in the interstitial cells of Cajal in the gallbladder of guinea pigs fed a lithogenic diet

Huang,Lei; Ding,Chao; Si,Xinmin

doi:10.3892/etm.2021.10255

Changes in the interstitial cells of Cajal in the gallbladder of guinea pigs fed a lithogenic diet

Authors:
- Lei Huang
- Chao Ding
- Xinmin Si
View Affiliations

Affiliations: Department of General Surgery, Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu 210008, P.R. China, Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
Published online on: June 2, 2021 https://doi.org/10.3892/etm.2021.10255
Article Number: 823
Copyright: © Huang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Cholesterol cholelithiasis is a common disease and gallbladder hypomotility may underlie its pathogenesis. Interstitial cells of Cajal (ICCs) in the gallbladder serve vital roles in regulating gallbladder motility. The aim of the present study was to investigate changes in gallbladder ICCs during the development of cholesterol cholelithiasis. A total of 40 male guinea pigs were randomly assigned to four groups and fed a standard diet (SD) or lithogenic diet (LD) for 2 or 8 weeks. The LD significantly increased the total cholesterol levels in the serum and bile, as well as the serum levels of high‑density lipoprotein‑cholesterol and low‑density lipoprotein‑cholesterol after 2 and 8 weeks. The LD also significantly increased and decreased the number of gallbladder ICCs at 2 and 8 weeks, respectively, by regulating the stem cell factor/C‑kit pathway. Moreover, the ultrastructure of gallbladder ICCs was significantly altered after 8 weeks, and the protein expression levels of connexin 43 in the gallbladder were differentially altered after 2 and 8 weeks. Finally, cholecystokinin receptor type A (CCK1R) expression in the gallbladder was assessed. In gallbladder ICCs, its expression was significantly increased and decreased after 2 and 8 weeks, respectively. In conclusion, these results demonstrate that the density, ultrastructure and CCK1R expression levels of gallbladder ICCs are differentially altered at various stages of cholesterol cholelithiasis progression, indicating that gallbladder ICCs may be considered a potential therapeutic target for treatment of cholesterol cholelithiasis.

View Figures

View References

1	Munoz LE, Boeltz S, Bilyy R, Schauer C, Mahajan A, Widulin N, Gruneboom A, Herrmann I, Boada E, Rauh M, et al: Neutrophil extracellular traps initiate gallstone formation. Immunity. 51:443–450.e4. 2019.PubMed/NCBI View Article : Google Scholar
2	Cai JS, Qiang S and Bao-Bing Y: Advances of recurrent risk factors and management of choledocholithiasis. Scand J Gastroenterol. 52:34–43. 2017.PubMed/NCBI View Article : Google Scholar
3	Figueiredo JC, Haiman C, Porcel J, Buxbaum J, Stram D, Tambe N, Cozen W, Wilkens L, Le Marchand L and Setiawan VW: Sex and ethnic/racial-specific risk factors for gallbladder disease. BMC Gastroenterol. 17(153)2017.PubMed/NCBI View Article : Google Scholar
4	Chen CH, Lin CL and Kao CH: Association between Hashimoto's thyroiditis and cholelithiasis: A retrospective cohort study in Taiwan. BMJ Open. 8(e020798)2018.PubMed/NCBI View Article : Google Scholar
5	Lammert F, Gurusamy K, Ko CW, Miquel JF, Mendez-Sanchez N, Portincasa P, van Erpecum KJ, van Laarhoven CJ and Wang DQ: Gallstones. Nat Rev Dis Primers. 2(16024)2016.PubMed/NCBI View Article : Google Scholar
6	Wang HH, Portincasa P, Liu M, Tso P, Samuelson LC and Wang DQ: Effect of gallbladder hypomotility on cholesterol crystallization and growth in CCK-deficient mice. Biochim Biophys Acta. 1801:138–146. 2010.PubMed/NCBI View Article : Google Scholar
7	Pasternak A, Szura M, Gil K and Matyja A: Interstitial cells of Cajal-systematic review. Folia Morphol. 75:281–286. 2016.PubMed/NCBI View Article : Google Scholar
8	Radenkovic G, Radenkovic D and Velickov A: Development of interstitial cells of Cajal in the human digestive tract as the result of reciprocal induction of mesenchymal and neural crest cells. J Cell Mol Med. 22:778–785. 2018.PubMed/NCBI View Article : Google Scholar
9	Chen L and Yu B: Telocytes and interstitial cells of Cajal in the biliary system. J Cell Mol Med. 22:3323–3329. 2018.PubMed/NCBI View Article : Google Scholar
10	Pasternak A, Gil K, Matyja A, Gajda M, Sztefko K, Walocha JA, Kulig J and Thor P: Loss of gallbladder interstitial Cajal-like cells in patients with cholelithiasis. Neurogastroenterol Motil. 25:e17–e24. 2013.PubMed/NCBI View Article : Google Scholar
11	Spetana J, Lipinski A and Jelen M: Comparison of the ICC location in the gallbladder wall in patients with cholelithiasis and patients with non-calculous changes. Pol J Pathol. 70:205–209. 2019.PubMed/NCBI View Article : Google Scholar
12	Fan Y, Wu S, Fu B, Weng C and Wang X: The role of interstitial Cajal-like cells in the formation of cholesterol stones in guinea pig gallbladder. Hepatol Int. 9:612–620. 2015.PubMed/NCBI View Article : Google Scholar
13	Konno K, Takahashi-Iwanaga H, Uchigashima M, Miyasaka K, Funakoshi A, Watanabe M and Iwanaga T: Cellular and subcellular localization of cholecystokinin (CCK)-1 receptors in the pancreas, gallbladder, and stomach of mice. Histochem Cell Biol. 143:301–312. 2015.PubMed/NCBI View Article : Google Scholar
14	Rathore RM, Angotzi AR, Jordal AE and Ronnestad I: Cholecystokinin receptors in Atlantic salmon: Molecular cloning, gene expression, and structural basis. Physiol Rep. 1(e00069)2013.PubMed/NCBI View Article : Google Scholar
15	Xu D, Yu BP, Luo HS and Chen LD: Control of gallbladder contractions by cholecystokinin through cholecystokinin-A receptors on gallbladder interstitial cells of Cajal. World J Gastroenterol. 14:2882–2887. 2008.PubMed/NCBI View Article : Google Scholar
16	Tharp KM, Khalifeh-Soltani A, Park HM, Yurek DA, Falcon A, Wong L, Feng R, Atabai K and Stahl A: Prevention of gallbladder hypomotility via FATP2 inhibition protects from lithogenic diet-induced cholelithiasis. Am J Physiol Gastrointest Liver Physiol. 310:G855–G864. 2016.PubMed/NCBI View Article : Google Scholar
17	Liu M, Liu C, Chen H, Huang X, Zeng X, Zhou J and Mi S: Prevention of cholesterol gallstone disease by schaftoside in lithogenic diet-induced C57BL/6 mouse model. Eur J Pharmacol. 815:1–9. 2017.PubMed/NCBI View Article : Google Scholar
18	Zheng Y, Xu M, Heianza Y, Ma W, Wang T, Sun D, Albert CM, Hu FB, Rexrode KM, Manson JE and Qi L: Gallstone disease and increased risk of mortality: Two large prospective studies in US men and women. J Gastroenterol Hepatol. 33:1925–1931. 2018.PubMed/NCBI View Article : Google Scholar
19	Lee S, Kweon OK and Kim WH: Associations between serum leptin levels, hyperlipidemia, and cholelithiasis in dogs. PLoS One. 12(e0187315)2017.PubMed/NCBI View Article : Google Scholar
20	Di Ciaula A, Garruti G, Fruhbeck G, De Angelis M, de Bari O, Wang DQ, Lammert F and Portincasa P: The role of diet in the pathogenesis of cholesterol gallstones. Curr Med Chem. 26:3620–3638. 2019.PubMed/NCBI View Article : Google Scholar
21	Wu X, Liang X, Du Y, Zhang Y, Yang M, Gong W, Liu B, Dong J, Zhang N and Zhang H: Prevention of gallstones by Lidan Granule: Insight into underlying mechanisms using a guinea pig model. Biomed Rep. 5:50–56. 2016.PubMed/NCBI View Article : Google Scholar
22	Rong ZH, Chen HY, Wang XX, Wang ZY, Xian GZ, Ma BZ, Qin CK and Zhang ZH: Effects of sphincter of Oddi motility on the formation of cholesterol gallstones. World J Gastroenterol. 22:5540–5547. 2016.PubMed/NCBI View Article : Google Scholar
23	Zheng H, Drumm BT, Zhu MH, Xie Y, O'Driscoll KE, Baker SA, Perrino BA, Koh SD and Sanders KM: Na⁺/Ca2⁺ exchange and pacemaker activity of interstitial cells of Cajal. Front Physiol. 11(230)2020.PubMed/NCBI View Article : Google Scholar
24	Sanders KM, Ward SM and Koh SD: Interstitial cells: Regulators of smooth muscle function. Physiol Rev. 94:859–907. 2014.PubMed/NCBI View Article : Google Scholar
25	Huang ZP, Qiu H and Yu BP: Distribution changes of interstitial cells of Cajal during cholesterol gallstone formation in guinea pigs fed a high cholesterol diet. Int J Clin Exp Pathol. 11:1653–1659. 2018.PubMed/NCBI
26	Chai Y, Huang Y, Tang H, Tu X, He J, Wang T, Zhang Q, Xiong F, Li D and Qiu Z: Role of stem cell growth factor/c-Kit in the pathogenesis of irritable bowel syndrome. Exp Ther Med. 13:1187–1193. 2017.PubMed/NCBI View Article : Google Scholar
27	Fan Y, Wu S, Fu B, Yan X, Wang X and Zhang W: Decreased expression of stem cell factor mRNA and protein in the gallbladders of guinea pigs fed on high cholesterol diet. Int J Clin Exp Med. 8:6379–6383. 2015.PubMed/NCBI
28	Wang L, Liang Y, Chen Q, Ahmed N, Wang F, Hu B and Yang P: Identification and distribution of the interstitial cells of Cajal in the abomasum of goats. Cell Transplant. 27:335–344. 2018.PubMed/NCBI View Article : Google Scholar
29	Wang HH, Portincasa P and Wang DQ: Update on the molecular mechanisms underlying the effect of cholecystokinin and cholecystokinin-1 receptor on the formation of cholesterol gallstones. Curr Med Chem. 26:3407–3423. 2019.PubMed/NCBI View Article : Google Scholar
30	Xu GQ, Xu CF, Chen HT, Liu S, Teng XD, Xu GY and Yu CH: Association of caveolin-3 and cholecystokinin A receptor with cholesterol gallstone disease in mice. World J Gastroenterol. 20:9513–9518. 2014.PubMed/NCBI View Article : Google Scholar