Open Access

Abnormal differentiation of stem cells into enteroendocrine cells in rats with DSS-induced colitis

  • Authors:
    • Magdy El‑Salhy
    • Kazuo Umezawa
    • Jan Gunnar Hatlebakk
    • Odd Helge Gilja
  • View Affiliations

  • Published online on: March 1, 2017     https://doi.org/10.3892/mmr.2017.6266
  • Pages: 2106-2112
  • Copyright: © El‑Salhy et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The present study aimed to determine whether there is an association between abnormalities in enteroendocrine cells in dextran sulfate sodium (DSS)‑induced colitis and the clonogenic and/or proliferative activities of stem cells. A total of 48 male Wistar rats were divided into four groups. Animals in the control group were provided with normal drinking water, whereas DSS colitis was induced in the remaining three groups. The rats with DSS‑induced colitis were randomized into the following three groups: i) DSS group, which received 0.5 ml 0.5% carboxymethyl cellulose (CMC; vehicle); ii) DSS‑G group, which was treated with 3-[(dodecylthiocarbonyl)-methyl]-glutarimide at 20 mg/kg body weight in 0.5% CMC; and iii) DSS‑Q group, which was treated with dehydroxymethylepoxyquinomicin at 15 mg/kg body weight in 0.5% CMC. Treatments were administered intraperitoneally twice daily for 5 days in all groups. Subsequently, tissue samples from the colon were stained with hematoxylin‑eosin, or immunostained for chromogranin A (CgA), Musashi 1 (Msi1), Math‑1, neurogenin 3 (Neurog3) and neurogenic differentiation D1 (NeuroD1). The densities of CgA, Msi1‑, Math‑1‑, Neurog3‑ and NeuroD1-immunoreactive cells were determined. DTCM‑G, and DHMEQ ameliorated the inflammation in DSS‑induced colitis. The density of CgA‑, Neurog3‑ and NeuroD1‑immunoreactive cells was significantly higher in the DSS group compared with in the control group, and the density of CgA cells was correlated with the densities of Neurog3‑ and NeuroD1-immunoreactive cells. There were no significant differences in the densities of Msi1‑ and Math‑1‑immunoreactive cells among the four experimental groups. The elevated densities of enteroendocrine cells detected in DSS‑induced colitis may be due to the increased differentiation of early enteroendocrine progenitors during secretory lineage. It is probable that the DSS‑induced inflammatory processes trigger certain signaling pathways, which control differentiation of the stem‑cell secretory lineage into mature enteroendocrine cells.

Introduction

Inflammatory bowel disease (IBD) is a chronic disease that consists of ulcerative colitis (UC) and Crohn's disease (14). The clinical course of IBD varies markedly, from frequent relapses, to chronic active disease, to years of complete remission (5). At present, the etiology of IBD is not completely understood (68). There are at least five distinct types of enteroendocrine cell in the large intestine, which are arranged between the epithelial cells lining the intestinal lumen (9,10). These cells regulate intestinal motility, secretion and absorption, as well as visceral sensitivity, local immune defense, cell proliferation and appetite (9,1126). The enteroendocrine cells in the large intestine are abnormal in patients with IBD and in animal models of IBD (24,2742). Interactions between the hormones secreted by the large intestine enteroendocrine cells and the immune system have previously been debated, and it has been speculated that these interactions serve a critical role in the pathophysiology of IBD (4345).

The cause of abnormalities in the large intestine enteroendocrine cells in IBD is not currently known. Abnormal intestinal enteroendocrine cells have been reported in congenital malabsorptive diarrhea alongside mutated transcription factor Neurogenin 3 (Neurog3), and in mutant mice with ablation of Neurog3 (46). The present study aimed to investigate whether the abnormalities observed in intestinal enteroendocrine cells in dextran sulfate sodium (DSS)-induced colitis are associated with abnormalities in the clonogenic and/or proliferative activities of stem cells (47). Furthermore, it was investigated whether the alterations in enteroendocrine cells and stem cells may be restored by treatment with two anti-inflammatory agents: 3-[(dodecylthiocarbonyl)-methyl]-glutarimide (DTCM-G) and dehydroxymethylepoxyquinomicin (DHMEQ). These agents have been demonstrated to exert potent anti-inflammatory activity in animal models (48,49).

Materials and methods

Rats

A total of 48 male Wistar rats (6 weeks old; Hannover GALAS; Taconic Europe A/S, Lille Skensved, Denmark) with a mean body weight of 290 g (range, 238–385 g) were housed in Macrolon III cages with ad libitum access to food and water. The rats were fed a standard diet (B&K Universal Limited, Hull, UK), and were maintained under the following conditions: Temperature between 20 and 22°C, relative humidity between 50 and 60%, and 12/12-h light/dark cycle.

The animals were allowed to acclimate in the animal house for ≥1 week prior to experimentation, and were then divided into 4 groups, each containing 12 rats. Rats in the control group were provided with normal drinking water for 7 days, whereas colitis was induced in the other three groups using DSS, as previously described (50,51). Briefly, the rats were provided with distilled drinking water containing 5% DSS (40 kD; TDB Consultancy AB, Uppsala, Sweden) for 7 days. The rats with DSS-induced colitis were randomized into the following three groups: i) DSS group, which received 0.5 ml 0.5% carboxymethyl cellulose (CMC; vehicle); ii) DSS-G group, which was treated with DTCM-G at 20 mg/kg body weight in 0.5% CMC; and iii) DSS-Q group, which was treated with DHMEQ at 15 mg/kg body weight in 0.5% CMC. Treatments were administered intraperitoneally twice daily for 5 days in all groups. DTCM-G and DHMEQ were synthesized as described previously (5255). The rats were monitored frequently, and those that showed any signs of pain were injected subcutaneously with 1 ml Temgesic solution (containing 0.3 g/ml Temgesic; Merck & Co., Inc., Kenilworth, NJ, USA) as an analgesic.

At the end of the 5-day treatment period, rats were sacrificed by CO2 inhalation, the colon was collected, and tissue samples were obtained from the lower part of the colon for subsequent examinations. The present study was approved by the local ethical committee at the University of Bergen for the Protection of Vertebrate Animals used for Experimental and Other Scientific Purposes (Bergen, Norway; project no. 20124629).

Histopathology and immunohistochemistry

The tissue samples were fixed in 4% buffered paraformaldehyde, embedded in paraffin, and cut into 5 mm sections. The sections were stained with hematoxylin and eosin, or immunostained using the ultraView Universal DAB Detection kit (version 1.02.0018; Ventana Medical Systems, Inc., Tucson, AZ, USA) and the BenchMark Ultra IHC/ISH staining module (Ventana Medical Systems, Inc.). The sections were incubated with the following primary antibodies for 32 min at 37°C: Monoclonal mouse anti-N-terminal of purified chromogranin A (CgA; 1:1,500; cat. no. M869; Dako Denmark A/S, Glostrup, Denmark); polyclonal rabbit anti-residues 5–21 [APQPGLASPDSPHDPCK] of the human, mouse and rat Musashi 1 (Msi1) protein (1:100; cat. no. NB100-1759; R&D Systems Europe, Abingdon, UK); polyclonal rabbit anti-synthetic peptide surrounding amino acid 190 of human Math-1 (1:50; code no. 3658-100; BioVision, Inc., Milpitas, CA, USA); polyclonal rabbit anti-KLH-conjugated synthetic peptide between 40–69 amino acids from the N-terminal region of human Neurog3 (1:50; cat. no. PA5-11893, Thermo Fisher, Oslo, Norway); and polyclonal rabbit anti-recombinant full-length human neurogenic differentiation D1 (NeuroD1; 1:50; cat. no. PA5-47381; Thermo Fisher). All of these antibodies detect antigens in humans and rats.

Quantification

The number of CgA-, Msi1-, Math-1-, Neurog3- and NeuroD1-immunoreactive cells, the number of crypts, and the area containing epithelial cells were counted in ten randomly selected microscopic fields using a light microscope (BX 43). Measurements were performed using cellSens imaging software (version 1.7; Olympus Corporation, Tokyo, Japan). This morphometric method has previously been validated (56). The number of immunoreactive cells and crypts in each field were counted manually by pointing and clicking the computer mouse, whereas the area of epithelial cells was determined by manual drawing using the computer mouse. A ×40 objective was used, for which each frame (field) on the monitor represented a tissue area of 0.035 mm2. The density of CgA was expressed as the number of immunoreactive endocrine cells per square millimeter of epithelium, the density of Msi1 was expressed as the number of immunoreactive cells per crypt, and the densities of Math-1, Neurog3 and NeuroD1 were expressed as the number of immunoreactive cells per field. Immunostained sections were coded, and measurements were performed by the same individual (M.E-S.), who was blinded to the identity of the sections.

Statistical analysis

The Kruskal-Wallis nonparametric test and Dunn's post hoc test were used to compare between the control, DSS, DSS-G and DSS-Q groups. Correlations between abnormalities/alterations in the densities of CgA-, Neurog3-, and NeuroD1-immunoreactive cells were determined using the nonparametric Spearman correlation test. Data are presented as the mean ± standard error of the mean. P<0.05 was considered to indicate a statistically significant difference.

Results

The colon samples collected from rats in the control, DSS-G and DSS-Q groups appeared histopathologically normal; however, in the DSS group, disturbed mucosal architecture, crypt abscesses, edema, bleeding and immune cell infiltration were observed (Fig. 1).

CgA immunostaining

CgA-immunoreactive cells were detected in crypts and alongside the gland of Lieberkühn. The cell densities in the control, DSS, DSS-G and DSS-Q groups were 113.0±20.4, 319.1±32.0, 123.9±22.6 and 141.3±14.3 cells/mm2 epithelium, respectively (Kruskal-Wallis test, P<0.0001; Figs. 2 and 3). Dunn's test indicated that the density of CgA-immunoreactive cells was significantly higher in the DSS group compared with in the control group (P<0.0001). The densities of CgA in DSS-G and DSS-Q did not differ from that of controls (P=0.9, and 0.1, respectively). The CgA-immunoreactive cell density was correlated with the densities of Neurog3- and NeuroD1-immunoreactive cells (r=0.8; P=0.006 for both).

Msi1 immunostaining

Msi1-immunoreactive cells were observed exclusively in the crypts of the gland of Lieberkühn. The cell densities in the control, DSS, DSS-G and DSS-Q groups were 4.9±0.5, 4.8±0.5, 5.1±0.6 and 5.0±0.6 cells/crypt, respectively (Kruskal-Wallis test, P=0.98; Fig. 4).

Math-1 immunostaining

Math-1-immunoreactive cells were observed in the crypts and alongside the gland of Lieberkühn. The cell densities in the control, DSS, DSS-G and DSS-Q groups were 80.2±10.4, 101.6±10.7, 99.1±8.3 and 100.1±11.3 cells/field, respectively (Kruskal-Wallis test, P=0.41; Fig. 4).

Neurog3 immunostaining

Neurog3-immunoreactive cells were detected in the crypts and alongside the gland of Lieberkühn (Figs. 4 and 5). The cell densities were 79.1±11.1, 223.1±36.0, 103.8±12.4 and 77.3±10.9 cells/field in the control, DSS, DSS-G and DSS-Q groups, respectively (Kruskal-Wallis test, P=0.002). The Neurog3-immunoreactive cell density was significantly higher in the DSS group compared with in the control group (Dunn's test: P=0.0002; Fig. 4C). There was no statistically significant difference between controls and DSS-G and DSS-Q regarding Neurog3 cell density (P=0.1, and 0.7, respectively).

NeuroD1 immunostaining

Similar to Neurog3, NeuroD1-immunoreactive cells were observed in the crypts and alongside the gland of Lieberkühn. The cell densities were 73.3±10.7, 217.3±24.4, 105.8±11.8 and 79.1±10.7 cells/field in the control, DSS, DSS-G and DSS-Q groups, respectively (Kruskal-Wallis test, P=0.0001). The density of NeuroD1-immunoreactive cells was significantly higher in the DSS group compared with in the control group (Dunn's test, P=0.0002; Fig. 4). The densities of NeuroD1 in DSS-G, and DSS-Q did not differ from that of controls (P=0.07, and 0.9, respectively).

Discussion

CgA is a general marker for enteroendocrine cells (57). In the present study, the density of CgA-immunoreactive cells in the large intestine was significantly elevated in rats with DSS-induced colitis, which is in agreement with previously reported observations (47). DSS-induced colitis is an animal model that is very similar, but not identical, to human UC (58). The density of CgA-immunoreactive cells in the large intestine has also been reported to be higher in patients with UC compared with in healthy subjects (27).

The intestine contains between 4 and 6 stem cells per crypt, and these cells exhibit two types of activity: i) Dividing into new stem cells (self-renewal, clonogeny) and ii) differentiating into all types of epithelial cell (differentiation) (5971). The differentiating stem cell progeny includes two lineages: Secretory and absorptive. The secretory lineage gives rise to goblet, endocrine and Paneth cells, whereas the absorptive lineage gives rise to absorptive enterocytes (5971). Msi1 is a transcription factor expressed by intestinal stem cells and their early progeny (7174). In the present study, the density of Msi1-immunoreactive cells did not differ between rats in the DSS group and those in the control group, thus indicating that the clonogenic activity of the stem cells was not affected by inflammation.

Math-1 is expressed by an early progenitor in the secretory lineage, and Math−/− mice lack secretory cells (75). The present study indicated that the density of Math-1-immunoreactive cells did not significantly differ between rats in the DSS group and those in the control group. These findings suggested that inflammation does not interfere with early secretory lineage differentiation.

Neurog3 is expressed in endocrine progenitor cells, which direct the differentiation of secretory progenitors into endocrine cells (46). Neurog3−/− mice possess normal densities of goblet and Paneth cells; however, they possess no pancreatic endocrine or enteroendocrine cells (46,76,77). NeuroD1 is a transcription factor that is expressed by cells derived from Neurog3 progenitors (78,79). Mice deficient in NeuroD1 do not possess a subgroup of enteroendocrine cells (46,80). In the present study, the densities of Neurog3- and NeuroD1-immunoreactive cells were higher in DSS-induced rats compared with in control rats. Furthermore, this elevation was strongly correlated with the increased CgA-immunoreactive cell density. This finding provided evidence to suggest that the increased density of enteroendocrine cells observed following DSS-induced colitis may be caused by an increase in the differentiation of early enteroendocrine progenitors during the secretory lineage. Intestinal stem cell proliferation is regulated by numerous signaling pathways (71). It is probable that the DSS-induced inflammatory processes trigger certain signaling pathways, which control the differentiation of the stem-cell secretory lineage into mature enteroendocrine cells.

The present study confirmed the findings of previous studies, that DTCM-G and DHME exhibit potent anti-inflammatory activity in animal models of UC (48,49). Stem cells differentiate rapidly into mature intestinal cells; this process typically takes 2–3 days (72). This may explain why, in the present study, treating rats with DSS-induced colitis with the anti-inflammatory agents DTCM-G and DHME for only 5 days restored the densities of CgA, Neurog3- and NeuroD1-immunoreactive cells to those of the control group. The rapid proliferation and differentiation of epithelial cells are disturbed by inflammation, which causes impairment in epithelial barrier function (8184). Polyphenols, which is quite different from DTCM-G and DHME, exert a protective effect on epithelial cells and consequently suppress the inflammatory response (8183).

In conclusion, the present study demonstrated that the elevated densities of enteroendocrine cells detected in DSS-induced colitis are probably due to increased differentiation of early enteroendocrine progenitors during the secretory lineage. It is likely that inflammatory processes trigger certain signaling pathways that control differentiation of the stem-cell secretory lineage into mature enteroendocrine cells. In addition, this process appears to be responsive to short-term anti-inflammatory treatment. It is probable that stem cell transplantation may be an effective treatment for patients with IBD, that have not responded to current available treatment.

Acknowledgements

The present study was supported by grants from Helse-Fonna (grant no. 40415) and Helse-Vest (grant no. 911978), Norway.

References

1 

Prantera C and Marconi S: Glucocorticosteroids in the treatment of inflammatory bowel disease and approaches to minimizing systemic activity. Therap Adv Gastroenterol. 6:137–156. 2013. View Article : Google Scholar : PubMed/NCBI

2 

Cosnes J, Gower-Rousseau C, Seksik P and Cortot A: Epidemiology and natural history of inflammatory bowel diseases. Gastroenterology. 140:1785–1794. 2011. View Article : Google Scholar : PubMed/NCBI

3 

Podolsky DK: Inflammatory bowel disease. N Engl J Med. 347:417–429. 2002. View Article : Google Scholar : PubMed/NCBI

4 

Podolsky DK: The current future understanding of inflammatory bowel disease. Best Pract Res Clin Gastroenterol. 16:933–943. 2002. View Article : Google Scholar : PubMed/NCBI

5 

Carter MJ, Lobo AJ and Travis SP: IBD Section, British Society of Gastroenterology: Guidelines for the management of inflammatory bowel disease in adults. Gut 53 Suppl. 5:V1–V16. 2004. View Article : Google Scholar

6 

Danese S and Fiocchi C: Etiopathogenesis of inflammatory bowel diseases. World J Gastroenterol. 12:4807–4812. 2006.PubMed/NCBI

7 

Nunes T, Fiorino G, Danese S and Sans M: Familial aggregation in inflammatory bowel disease: Is it genes or environment? World J Gastroenterol. 17:2715–2722. 2011. View Article : Google Scholar : PubMed/NCBI

8 

El-Salhy M, Gundersen D, Hatlebakk JG and Hausken T: Clinical presentation, diagnosis, pathogenesis and treatment options for lymphocytic colitis (Review). Int J Mol Med. 32:263–270. 2013.PubMed/NCBI

9 

El-Salhy M, Seim I, Chopin L, Gundersen D, Hatlebakk JG and Hausken T: Irritable bowel syndrome: The role of gut neuroendocrine peptides. Front Biosci (Elite Ed). 4:2783–2800. 2012.PubMed/NCBI

10 

El-Salhy M, Gundersen D, Hatlebakk JG and Hausken T: Irritable bowel syndrome: Diagnosis, pathogenesis, and treatment options. Nova Science Publishers, Inc., New York; 2012

11 

El-Salhy M: Irritable bowel syndrome: Diagnosis and pathogenesis. World J Gastroenterol. 18:5151–5163. 2012.PubMed/NCBI

12 

El-Salhy M, Ostgaard H, Gundersen D, Hatlebakk JG and Hausken T: The role of diet in the pathogenesis and management of irritable bowel syndrome (Review). Int J Mol Med. 29:723–731. 2012.PubMed/NCBI

13 

Mawe GM, Coates MD and Moses PL: Review article: Intestinal serotonin signalling in irritable bowel syndrome. Aliment Pharmacol Ther. 23:1067–1076. 2006. View Article : Google Scholar : PubMed/NCBI

14 

Wade PR, Chen J, Jaffe B, Kassem IS, Blakely RD and Gershon MD: Localization and function of a 5-HT transporter in crypt epithelia of the gastrointestinal tract. J Neurosci. 16:2352–2364. 1996.PubMed/NCBI

15 

Gershon MD and Tack J: The serotonin signaling system: From basic understanding to drug development for functional GI disorders. Gastroenterology. 132:397–414. 2007. View Article : Google Scholar : PubMed/NCBI

16 

Gershon MD: 5-Hydroxytryptamine (serotonin) in the gastrointestinal tract. Curr Opin Endocrinol Diabetes Obes. 20:14–21. 2013. View Article : Google Scholar : PubMed/NCBI

17 

Gershon MD: Serotonin is a sword and a shield of the bowel: Serotonin plays offense and defense. Trans Am Clin Climatol Assoc. 123:268–280. 2012.PubMed/NCBI

18 

El-Salhy M, Mazzawi T, Gundersen D, Hatlebakk JG and Hausken T: The role of peptide YY in gastrointestinal diseases and disorders (review). Int J Mol Med. 31:275–282. 2013.PubMed/NCBI

19 

Dubrasquet M, Bataille D and Gespach C: Oxyntomodulin (glucagon-37 or bioactive enteroglucagon): A potent inhibitor of pentagastrin-stimulated acid secretion in rats. Biosci Rep. 2:391–395. 1982. View Article : Google Scholar : PubMed/NCBI

20 

Schjoldager B, Mortensen PE, Myhre J, Christiansen J and Holst JJ: Oxyntomodulin from distal gut. Role in regulation of gastric and pancreatic functions. Dig Dis Sci. 34:1411–1419. 1989. View Article : Google Scholar : PubMed/NCBI

21 

Schjoldager BT, Baldissera FG, Mortensen PE, Holst JJ and Christiansen J: Oxyntomodulin: A potential hormone from the distal gut. Pharmacokinetics and effects on gastric acid and insulin secretion in man. Eur J Clin Invest. 18:499–503. 1988. View Article : Google Scholar : PubMed/NCBI

22 

Dakin CL, Small CJ, Batterham RL, Neary NM, Cohen MA, Patterson M, Ghatei MA and Bloom SR: Peripheral oxyntomodulin reduces food intake and body weight gain in rats. Endocrinology. 145:2687–2695. 2004. View Article : Google Scholar : PubMed/NCBI

23 

Wynne K, Park AJ, Small CJ, Patterson M, Ellis SM, Murphy KG, Wren AM, Frost GS, Meeran K, Ghatei MA and Bloom SR: Subcutaneous oxyntomodulin reduces body weight in overweight and obese subjects: A double-blind, randomized, controlled trial. Diabetes. 54:2390–2395. 2005. View Article : Google Scholar : PubMed/NCBI

24 

El-Salhy M and Hausken T: The role of the neuropeptide Y (NPY) family in the pathophysiology of inflammatory bowel disease (IBD). Neuropeptides. 55:134–144. 2016. View Article : Google Scholar

25 

Camilleri M: Peripheral mechanisms in irritable bowel syndrome. N Engl J Med. 367:1626–1635. 2012. View Article : Google Scholar : PubMed/NCBI

26 

Jianu CS, Fossmark R, Syversen U, Hauso Ø and Waldum HL: A meal test improves the specificity of chromogranin A as a marker of neuroendocrine neoplasia. Tumour Biol. 31:373–380. 2010. View Article : Google Scholar : PubMed/NCBI

27 

El-Salhy M, Danielsson A, Stenling R and Grimelius L: Colonic endocrine cells in inflammatory bowel disease. J Intern Med. 242:413–419. 1997. View Article : Google Scholar : PubMed/NCBI

28 

El-Salhy M, Gundersen D, Hatlebakk JG and Hausken T: Chromogranin a cell density as a diagnostic marker for lymphocytic colitis. Dig Dis Sci. 57:3154–3159. 2012. View Article : Google Scholar : PubMed/NCBI

29 

El-Salhy M, Gundersen D, Hatlebakk JG and Hausken T: High densities of serotonin and peptide YY cells in the colon of patients with lymphocytic colitis. World J Gastroenterol. 18:6070–6075. 2012. View Article : Google Scholar : PubMed/NCBI

30 

El-Salhy M, Lomholt-Beck B and Gundersen TD: High chromogranin A cell density in the colon of patients with lymphocytic colitis. Mol Med Rep. 4:603–605. 2011.PubMed/NCBI

31 

Moran GW, Pennock J and McLaughlin JT: Enteroendocrine cells in terminal ileal Crohn's disease. J Crohns Colitis. 6:871–880. 2012. View Article : Google Scholar : PubMed/NCBI

32 

Besterman HS, Mallinson CN, Modigliani R, Christofides ND, Pera A, Ponti V, Sarson DL and Bloom SR: Gut hormones in inflammatory bowel disease. Scand J Gastroenterol. 18:845–852. 1983. View Article : Google Scholar : PubMed/NCBI

33 

El-Salhy M, Suhr O and Danielsson A: Peptide YY in gastrointestinal disorders. Peptides. 23:397–402. 2002. View Article : Google Scholar : PubMed/NCBI

34 

Tari A, Teshima H, Sumii K, Haruma K, Ohgoshi H, Yoshihara M, Kajiyama G and Miyachi Y: Peptide YY abnormalities in patients with ulcerative colitis. Jpn J Med. 27:49–55. 1988. View Article : Google Scholar : PubMed/NCBI

35 

Sciola V, Massironi S, Conte D, Caprioli F, Ferrero S, Ciafardini C, Peracchi M, Bardella MT and Piodi L: Plasma chromogranin a in patients with inflammatory bowel disease. Inflamm Bowel Dis. 15:867–871. 2009. View Article : Google Scholar : PubMed/NCBI

36 

Bishop AE, Pietroletti R, Taat CW, Brummelkamp WH and Polak JM: Increased populations of endocrine cells in Crohn's ileitis. Virchows Arch A Pathol Anat Histopathol. 410:391–396. 1987. View Article : Google Scholar : PubMed/NCBI

37 

Manocha M and Khan WI: Serotonin and GI disorders: An update on clinical and experimental studies. Clin Transl Gastroenterol. 3:e132012. View Article : Google Scholar : PubMed/NCBI

38 

Stoyanova II and Gulubova MV: Mast cells and inflammatory mediators in chronic ulcerative colitis. Acta Histochem. 104:185–192. 2002. View Article : Google Scholar : PubMed/NCBI

39 

Yamamoto H, Morise K, Kusugami K, Furusawa A, Konagaya T, Nishio Y, Kaneko H, Uchida K, Nagai H, Mitsuma T and Nagura H: Abnormal neuropeptide concentration in rectal mucosa of patients with inflammatory bowel disease. J Gastroenterol. 31:525–532. 1996. View Article : Google Scholar : PubMed/NCBI

40 

Payer J, Huorka M, Duris I, Mikulecky M, Kratochvílová H, Ondrejka P and Lukác L: Plasma somatostatin levels in ulcerative colitis. Hepatogastroenterology. 41:552–553. 1994.PubMed/NCBI

41 

Watanabe T, Kubota Y, Sawada T and Muto T: Distribution and quantification of somatostatin in inflammatory disease. Dis Colon Rectum. 35:488–494. 1992. View Article : Google Scholar : PubMed/NCBI

42 

Koch TR, Carney JA, Morris VA and Go VL: Somatostatin in the idiopathic inflammatory bowel diseases. Dis Colon Rectum. 31:198–203. 1988. View Article : Google Scholar : PubMed/NCBI

43 

Khan WI and Ghia JE: Gut hormones: Emerging role in immune activation and inflammation. Clin Exp Immunol. 161:19–27. 2010.PubMed/NCBI

44 

Margolis KG and Gershon MD: Neuropeptides and inflammatory bowel disease. Curr Opin Gastroenterol. 25:503–511. 2009. View Article : Google Scholar : PubMed/NCBI

45 

Bampton PA and Dinning PG: High resolution colonic manometry-what have we learnt?-A review of the literature 2012. Curr Gastroenterol Rep. 15:3282013. View Article : Google Scholar : PubMed/NCBI

46 

Wang J, Cortina G, Wu SV, Tran R, Cho JH, Tsai MJ, Bailey TJ, Jamrich M, Ament ME, Treem WR, et al: Mutant neurogenin-3 in congenital malabsorptive diarrhea. N Engl J Med. 355:270–280. 2006. View Article : Google Scholar : PubMed/NCBI

47 

El-Salhy M and Umezawa K: Treatment with novel AP-1 and NF-κB inhibitors restores the colonic endocrine cells to normal levels in rats with DSS-induced colitis. Int J Mol Med. 37:556–564. 2016.PubMed/NCBI

48 

Funakoshi T, Yamashita K, Ichikawa N, Fukai M, Suzuki T, Goto R, Oura T, Kobayashi N, Katsurada T, Ichihara S, et al: A novel NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin, ameliorates inflammatory colonic injury in mice. J Crohns Colitis. 6:215–225. 2012. View Article : Google Scholar : PubMed/NCBI

49 

El-Salhy M, Umezawa K, Gilja OH, Hatlebakk JG, Gundersen D and Hausken T: Amelioration of severe TNBS induced colitis by novel AP-1 and NF-κB inhibitors in rats. Scientific World Journal. 2014:8138042014. View Article : Google Scholar : PubMed/NCBI

50 

Grimstad T, Bjørndal B, Cacabelos D, Aasprong OG, Omdal R, Svardal A, Bohov P, Pamplona R, Portero-Otin M, Berge RK and Hausken T: A salmon peptide diet alleviates experimental colitis as compared with fish oil. J Nutr Sci. 2:e22013. View Article : Google Scholar : PubMed/NCBI

51 

Stucchi AF, Shofer S, Leeman S, Materne O, Beer E, McClung J, Shebani K, Moore F, O'Brien M and Becker JM: NK-1 antagonist reduces colonic inflammation and oxidative stress in dextran sulfate-induced colitis in rats. Am J Physiol Gastrointest Liver Physiol. 279:G1298–G1306. 2000.PubMed/NCBI

52 

Ota E, Takeiri M, Tachibana M, Ishikawa Y, Umezawa K and Nishiyama S: Synthesis and biological evaluation of molecular probes based on the 9-methylstreptimidone derivative DTCM-glutarimide. Bioorg Med Chem Lett. 22:164–167. 2012. View Article : Google Scholar : PubMed/NCBI

53 

Takeiri M, Tachibana M, Kaneda A, Ito A, Ishikawa Y, Nishiyama S, Goto R, Yamashita K, Shibasaki S, Hirokata G, et al: Inhibition of macrophage activation and suppression of graft rejection by DTCM-glutarimide, a novel piperidine derived from the antibiotic 9-methylstreptimidone. Inflamm Res. 60:879–888. 2011. View Article : Google Scholar : PubMed/NCBI

54 

Ishikawa Y, Tachibana M, Matsui C, Obata R, Umezawa K and Nishiyama S: Synthesis and biological evaluation on novel analogs of 9-methylstreptimidone, an inhibitor of NF-kappaB. Bioorg Med Chem Lett. 19:1726–1728. 2009. View Article : Google Scholar : PubMed/NCBI

55 

Umezawa N, Matsumoto N, Iwama S, Kato N and Higuchi T: Facile synthesis of peptide-porphyrin conjugates: Towards artificial catalase. Bioorg Med Chem. 18:6340–6350. 2010. View Article : Google Scholar : PubMed/NCBI

56 

el-Salhy M, Sandstrom O, Näsström E, Mustajbasic M and Zachrisson S: Application of computer image analysis in endocrine cell quantification. Histochem J. 29:249–256. 1997. View Article : Google Scholar : PubMed/NCBI

57 

El-Salhy M, Gilja OH, Gundersen D, Hatlebakk JG and Hausken T: Duodenal chromogranin a cell density as a biomarker for the diagnosis of irritable bowel syndrome. Gastroenterol Res Pract. 2014:4628562014. View Article : Google Scholar : PubMed/NCBI

58 

Elson CO, Sartor RB, Tennyson GS and Riddell RH: Experimental models of inflammatory bowel disease. Gastroenterology. 109:1344–1367. 1995. View Article : Google Scholar : PubMed/NCBI

59 

Cardoso WV and Lü J: Regulation of early lung morphogenesis: Questions, facts and controversies. Development. 133:1611–1624. 2006. View Article : Google Scholar : PubMed/NCBI

60 

Darlington GJ: Molecular mechanisms of liver development and differentiation. Curr Opin Cell Biol. 11:678–682. 1999. View Article : Google Scholar : PubMed/NCBI

61 

Fausto N, Campbell JS and Riehle KJ: Liver regeneration. Hepatology. 43(2 Suppl 1): S45–S53. 2006. View Article : Google Scholar : PubMed/NCBI

62 

Rawlins EL and Hogan BL: Ciliated epithelial cell lifespan in the mouse trachea and lung. Am J Physiol Lung Cell Mol Physiol. 295:L231–L234. 2008. View Article : Google Scholar : PubMed/NCBI

63 

Zaret KS: Regulatory phases of early liver development: Paradigms of organogenesis. Nat Rev Genet. 3:499–512. 2002. View Article : Google Scholar : PubMed/NCBI

64 

Barker N, van Es JH, Kuipers J, Kujala P, van den Born M, Cozijnsen M, Haegebarth A, Korving J, Begthel H, Peters PJ and Clevers H: Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature. 449:1003–1007. 2007. View Article : Google Scholar : PubMed/NCBI

65 

Barker N, van de Wetering M and Clevers H: The intestinal stem cell. Genes Dev. 22:1856–1864. 2008. View Article : Google Scholar : PubMed/NCBI

66 

Cheng H and Leblond CP: Origin, differentiation and renewal of the four main epithelial cell types in the mouse small intestine. V. Unitarian theory of the origin of the four epithelial cell types. Am J Anat. 141:537–561. 1974. View Article : Google Scholar : PubMed/NCBI

67 

Le Douarin NM and Teillet MA: The migration of neural crest cells to the wall of the digestive tract in avian embryo. J Embryol Exp Morphol. 30:31–48. 1973.PubMed/NCBI

68 

Rawdon BB and Andrew A: Origin and differentiation of gut endocrine cells. Histol Histopathol. 8:567–580. 1993.PubMed/NCBI

69 

Hoffman J, Kuhnert F, Davis CR and Kuo CJ: Wnts as essential growth factors for the adult small intestine and colon. Cell Cycle. 3:554–557. 2004. View Article : Google Scholar : PubMed/NCBI

70 

Korinek V, Barker N, Moerer P, van Donselaar E, Huls G, Peters PJ and Clevers H: Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4. Nat Genet. 19:379–383. 1998. View Article : Google Scholar : PubMed/NCBI

71 

Montgomery RK and Breault DT: Small intestinal stem cell markers. J Anat. 213:52–58. 2008. View Article : Google Scholar : PubMed/NCBI

72 

Potten CS, Booth C, Tudor GL, Booth D, Brady G, Hurley P, Ashton G, Clarke R, Sakakibara S and Okano H: Identification of a putative intestinal stem cell and early lineage marker; musashi-1. Differentiation. 71:28–41. 2003. View Article : Google Scholar : PubMed/NCBI

73 

Kayahara T, Sawada M, Takaishi S, Fukui H, Seno H, Fukuzawa H, Suzuki K, Hiai H, Kageyama R, Okano H and Chiba T: Candidate markers for stem and early progenitor cells, Musashi-1 and Hes1, are expressed in crypt base columnar cells of mouse small intestine. FEBS Lett. 535:131–135. 2003. View Article : Google Scholar : PubMed/NCBI

74 

He XC, Yin T, Grindley JC, Tian Q, Sato T, Tao WA, Dirisina R, Porter-Westpfahl KS, Hembree M, Johnson T, et al: PTEN-deficient intestinal stem cells initiate intestinal polyposis. Nat Genet. 39:189–198. 2007. View Article : Google Scholar : PubMed/NCBI

75 

Yang Q, Bermingham NA, Finegold MJ and Zoghbi HY: Requirement of Math1 for secretory cell lineage commitment in the mouse intestine. Science. 294:2155–2158. 2001. View Article : Google Scholar : PubMed/NCBI

76 

Jenny M, Uhl C, Roche C, Duluc I, Guillermin V, Guillemot F, Jensen J, Kedinger M and Gradwohl G: Neurogenin3 is differentially required for endocrine cell fate specification in the intestinal and gastric epithelium. EMBO J. 21:6338–6347. 2002. View Article : Google Scholar : PubMed/NCBI

77 

Lee CS, Perreault N, Brestelli JE and Kaestner KH: Neurogenin 3 is essential for the proper specification of gastric enteroendocrine cells and the maintenance of gastric epithelial cell identity. Genes Dev. 16:1488–1497. 2002. View Article : Google Scholar : PubMed/NCBI

78 

Naya FJ, Huang HP, Qiu Y, Mutoh H, DeMayo FJ, Leiter AB and Tsai MJ: Diabetes, defective pancreatic morphogenesis and abnormal enteroendocrine differentiation in BETA2/neuroD-deficient mice. Genes Dev. 11:2323–2334. 1997. View Article : Google Scholar : PubMed/NCBI

79 

Ahlgren U, Jonsson J and Edlund H: The morphogenesis of the pancreatic mesenchyme is uncoupled from that of the pancreatic epithelium in IPF1/PDX1-deficient mice. Development. 122:1409–1416. 1996.PubMed/NCBI

80 

Schonhoff SE, Giel-Moloney M and Leiter AB: Minireview: Development and differentiation of gut endocrine cells. Endocrinology. 145:2639–2644. 2004. View Article : Google Scholar : PubMed/NCBI

81 

Yang G, Bibi S, Du M, Suzuki T and Zhu MJ: Regulation of the intestinal tight junction by natural polyphenols: A mechanistic perspective. Crit Rev Food Sci Nutr. Mar 23–2016.(Epub ahead of print). View Article : Google Scholar

82 

Yang G, Wang H, Kang Y and Zhu MJ: Grape seed extract improves epithelial structure and suppresses inflammation in ileum of IL-10-deficient mice. Food Funct. 5:2558–2563. 2014. View Article : Google Scholar : PubMed/NCBI

83 

Yang G, Xue Y, Zhang H, Du M and Zhu MJ: Favourable effects of grape seed extract on intestinal epithelial differentiation and barrier function in IL10-deficient mice. Br J Nutr. 114:15–23. 2015. View Article : Google Scholar : PubMed/NCBI

84 

Yang GB and Lackner AA: Proximity between 5-HT secreting enteroendocrine cells and lymphocytes in the gut mucosa of rhesus macaques (Macaca mulatta) is suggestive of a role for enterochromaffin cell 5-HT in mucosal immunity. J Neuroimmunol. 146:46–49. 2004. View Article : Google Scholar : PubMed/NCBI

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April-2017
Volume 15 Issue 4

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Spandidos Publications style
El‑Salhy M, Umezawa K, Hatlebakk JG and Gilja OH: Abnormal differentiation of stem cells into enteroendocrine cells in rats with DSS-induced colitis. Mol Med Rep 15: 2106-2112, 2017.
APA
El‑Salhy, M., Umezawa, K., Hatlebakk, J.G., & Gilja, O.H. (2017). Abnormal differentiation of stem cells into enteroendocrine cells in rats with DSS-induced colitis. Molecular Medicine Reports, 15, 2106-2112. https://doi.org/10.3892/mmr.2017.6266
MLA
El‑Salhy, M., Umezawa, K., Hatlebakk, J. G., Gilja, O. H."Abnormal differentiation of stem cells into enteroendocrine cells in rats with DSS-induced colitis". Molecular Medicine Reports 15.4 (2017): 2106-2112.
Chicago
El‑Salhy, M., Umezawa, K., Hatlebakk, J. G., Gilja, O. H."Abnormal differentiation of stem cells into enteroendocrine cells in rats with DSS-induced colitis". Molecular Medicine Reports 15, no. 4 (2017): 2106-2112. https://doi.org/10.3892/mmr.2017.6266