Open Access

Role of stem cell growth factor/c-Kit in the pathogenesis of irritable bowel syndrome (Review)

  • Authors:
    • Yuna Chai
    • Yusheng Huang
    • Hongmei Tang
    • Xing Tu
    • Jianbo He
    • Ting Wang
    • Qingye Zhang
    • Fen Xiong
    • Detang Li
    • Zhenwen Qiu
  • View Affiliations

  • Published online on: February 20, 2017     https://doi.org/10.3892/etm.2017.4133
  • Pages:1187-1193
  • Copyright: © Chai et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

0

Abstract

Irritable bowel syndrome (IBS) is a functional bowel disease with a complicated etiopathogenesis, often characterized by gastrointestinal motility disorder and high visceral sensitivity. IBS is a comprehensive multi‑systemic disorder, with the interaction of multiple factors, such as mental stress, intestinal function and flora, heredity, resulting in the disease. The existence of a common mechanism underlying the aforementioned factors is currently unknown. The lack of therapies that comprehensively address the disease symptoms, including abdominal pain and diarrhea, is a limitation of current IBS management. The current review has explored the role of the SCF/c‑Kit receptor/ligand system in IBS. The SCF/c-Kit system constitutes a classical ligand/receptor tyrosine kinase signaling system that mediates inflammation and smooth muscle contraction. Additionally, it provides trophic support to neural crest‑derived cell types, including the enteric nervous system and mast cells. The regulation of SCF/c‑Kit on the interstitial cells of Cajal (ICC) suggest that it may play a key role in the aberrant intestinal dynamics and high visceral sensitivity observed in IBS. The role of the SCF/c‑Kit system in intestinal motility, inflammation and nerve growth has been reported. From the available biomedical evidence on the pathogenesis of IBS, it has been concluded that the SCF-c-Kit system is a potential therapeutic target for rational drug design in the treatment of IBS.

Introduction

Irritable bowel syndrome (IBS) is one of the most prevalent chronic and functional bowel diseases, resulting in considerable misery across the globe (13). The disease is characterized by substantial abdominal pain and discomfort; however, it lacks anatomical or histological aberrations or consistent changes in clinical chemistry (4,5). The current incidence of IBS is between 7–21% worldwide, a phenomenon attributed to an increased pace of life and alterations in diet (6). Identified risk factors requiring further investigation include psychological stress, changes in social environment, noxious gut stimuli and specific dietary factors. Experimental and emerging treatments, including fecal transplantation, have also been linked to IBS pathogenesis (7), further demonstrating the need for more detailed study into the IBS risk factors. Greater understanding of factors associated with the disease is potentially critical for future improvements in disease prevention and therapy.

The obscurity of IBS pathogenesis is a hindrance to such progress, though it is generally accepted that high visceral sensitivity and disturbed gut motility, in combination with low-grade inflammation, cause IBS via neuroendocrine and immune dysfunction (8). However, identifying the factors that mediate this dysfunction is still a major challenge in current IBS research. Clues into the etiology of the disease may be provided by study into the neurotransmitter dynamics of the brain-gut axis and associated endocrinological factors (9,10), as well as the intestinal flora, though a single factor alone cannot explain the complexity of IBS pathogenesis. Nevertheless, research should provide important insights into pathomechanism of IBS that potentially lead to novel drug development for the treatment of IBS.

The available evidence suggests that stem cell factor (SCF) expression is increased in clinical IBS (11). The system composed of SCF and its cognate receptor, c-Kit, is a principal regulator of survival and functionality for a multitude of neural crest-derived cell types, in particular for those involved in visceral perception, smooth muscle contraction and inflammation (1214). Disorders of the neuro-endocrine-immunological network resulting from alterations in the SCF/c-Kit system provide an explanation for the high visceral sensitivity, abnormal bowel contraction strength and low-grade inflammation experienced in IBS, suggesting that this system may be an important target for intervention (15,16). In the present review, the current trends in IBS are investigated, highlighting the regulation of SCF/c-Kit.

Biological functions of the SCF/c-Kit system

The c-Kit receptor is the product of the c-kit proto-oncogene and belongs to the receptor tyrosine kinase (RTK) superfamily, with the members of this family being the cardinal regulators of cellular fate in the mammalian body (17). As an important member of the type III RTK family, it has a highly specific and restricted expression pattern, with prominent c-Kit levels expressed on the surface of hematopoietic cells, mast cells (MCs) and interstitial cells of Cajal (ICC) (18,19). The cognate ligand of c-Kit is SCF, alternatively known as dry factor or MC growth factor, which is synthesized in abundance by the gastrointestinal (GI) tract smooth muscle cells (SMCs) (20). The expression patterns of SCF and c-Kit are thus consistent with their potential involvement in IBS.

In the SCF/c-Kit mechanism, as presented in Fig. 1, extracellular SCF binds specifically with c-Kit, with few alternate receptors proposed. Following SCF binding, c-Kit homodimers are formed via activation of the enzymatic kinase domain within the receptor (21). This provokes autophosphorylation of tyrosine residues within the receptor's cytoplasmic C-termini. The phosphotyrosine residues serve as docking sites for receptor adaptor proteins, in turn provoking activation of a range of signal transduction pathways (22). These can involve the following signaling molecules: Phosphatidylinositol 3-kinase (PI3K), single-subunit small GTPases/extracellular regulated protein kinases (Ras/Erk), janus kinase/signal transducers and activators of transcription (JAK/STAT), phospholipase C (PLC)-γ and the tyrosine-protein kinase Src (16,22). Specific expression of genes typically results and a range of biological signals are initiated to regulate the survival, proliferation, differentiation, apoptosis, motility and migration of c-Kit bearing cells (22).

Regulation of the SCF/c-Kit system affects the function of a variety of cells

Cell lines regulated by the SCF/c-Kit system prominently include ICC, other enteric nerve cells (NCs) and MCs. In general, SCF is a trophic factor for neural crest derivatives, with similar effects on ICC in terms of differentiation and proliferation (23). SCF specifically increases expression of the key gap junction protein connexin 43 (Cx43), resulting in improved network function by promoting intercellular conduction of electric stimuli (24). Furthermore, SCF promotes MC hyperplasia and enhances the release of MC-derived pro-inflammatory mediators (2527). The main mediators released are histamine, serotonin and arachidonic acid-derived compounds (leukotrienes, prostaglandins (28), interleukin), which in turn reduce the integrity of the local microcirculation and elicit an inflammatory response of body (2931). Additionally, SCF increases the intrinsic pacemaker rhythm of ICC that regulates GI smooth muscle contraction, via phosphorylation of substance P (SP), neurokinin-1 (NK1), transient receptor potential vanilloid-1 (TRPV1) receptors and by promoting the conduction of pain signals towards the central nervous system (CNS) (32). When considering the consequences of alterations in these biological signals, a potential role of the SCF/c-Kit axis in IBS pathophysiology emerges. It can be argued that this axis contributes to the high visceral sensitivity, exaggerated contraction and inflammation observed in IBS, thus explaining how stress and psychological factors are related to abdominal pain and discomfort in IBS.

In this context, it is noteworthy that structural loss in the ICC is a potential factor in IBS pathogenesis (15,33). ICCs constitute an elaborate network of contraction-controlling cells, present in all muscle layers of the GI tract and other internal structures, including the stomach, small intestine, pancreas, colon and bladder, where they regulate a range of biological functions. Based on their morphology, distribution and anatomical relationship with nerve plexus and smooth muscle, ICC are categorized into four subtypes (34): i) Myenteric ICC (IC-MY), located between circular and longitudinal muscle layers of the stomach, small intestine, colon and other muscles (35); ii) submucosal ICC (IC-SM), distributed along the submucosal layer of the surficial colon circular beam (36); iii) deep muscular ICC, (IC-DMP), located between the inner thin layer and outer thick layer of the intramuscular ring, particularly in the small intestine (37); and iv) intramuscular ICC, (IC-IM), located in all areas of the muscle layers above (35). MY and IC-SM serve mainly as GI pacemakers. IC-DMP and IC-IM are typically associated with the transmission of enteric nerve signals. The ICC types constitute an intricate network, fundamental to GI electrophysiological activity (22). Importantly, cross-talk with the CNS exists and the ICC stimulate the sensory nerve of the GI tract through direct synaptic contact (3840). The ICC are key to gastroenterological function and, conversely, the SCF/c-Kit axis is important for the development and phenotypic differentiation of the ICC, as well as ICC membrane polarization and pacemaker activity. Thus, a defining role of the axis in transcriptional regulation effecting intestinal bowel movement and intestinal rhythm is possible (41). Indeed, in experimental rodents, neutralizing antibody targeting c-Kit resulted in major loss of ICC from the jejunum, whereas high-dose SCF reversed this effect (23). Together with the cardinal functionality of ICC in visceral motility (including pacemaker activity, regulation of peristaltic bowel movement and other aspects of smooth muscle cell functionality), these results indicate that key aspects of GI physiology require functional SCF/c-Kit signaling. Though it is noteworthy that the SCF/c-Kit axis controls mainly long-term changes in ICC physiology, where it is directly controlled by receptors for NK1, NO, 5-hydroxytryptamine (5-HT) and SP, expressed on the ICC surface.

Other cell types controlled by the SCF/c-Kit axis include MCs, a specific type of immune cell required for barrier protection in the intestinal mucosa. An important event in IBS pathogenesis is MC degranulation (42), whereby MC release 5-HT, histamine, TNF-α and various interleukins, all of which are known to aggravate intestinal inflammation and affect visceral perception (43). The development and migration of MCs depend on SCF. For instance, SCF promotes the adhesion and proliferation of MCs by regulating expression of intercellular adhesion molecule-1 (44). As a chemotactic factor of MCs, SCF may promote the regeneration of MC from CD34+ progenitor cells, MC survival and adhesion to the extracellular matrix (25). Importantly, histamine levels decline substantially when the SCF/c-Kit system is repressed and the SCF/c-Kit axis has been repeatedly identified as one of the most promising targets for controlling MC inflammation (26,45). Indeed, evidence suggests that SCF inhibition potentially lowers visceral sensitivity via modulation of the MC compartment (46).

Additionally, control of neuronal electrical activity is key to reducing excessive intestinal motility in IBS. The signaling pathway provoked by SCF/c-Kit activity maintains survival, proliferation and nutrition of the neural crest cells, as well as inducing their differentiation and migration (47). c-Kit expression is a typical characteristic of post-mitotic nerve cells in the early stages of lineage differentiation from neurons to glial cells. SCF stimulates nerve regeneration both in experimental rodents and in vitro (48). Although indirect, these associations point to a central role of the SCF/c-Kit axis in organizing neural networks and represent targets for IBS treatment.

ICC, MC and NC are not independent structures and undergo interactions when IBS occurs throughout the nervous system (NS), digestive system, immune system and other regions (4952). They constitute a large and intricate network system, potentially of critical importance in IBS due to its control of a range of intestinal functions, including visceral sensitivity and inflammatory responses. However, it is also important to note that the ICC, MCs and NCs are not the sole targets of SCF/c-Kit activity, with other cell targets of SCF/c-Kit having potential involvement in IBS.

Relationship between the SCF/c-Kit axis and neuroendocrine-immune regulation in IBS

SCF/c-Kit and neurological disorders

Neurological disorders, including those of the enteric nervous system (ENS), the autonomic nervous system (ANS) and the CNS, contribute to visceral hypersensitivity and GI motility disorder in IBS (53). Upon stimulation by intestinal irritation and/or psychological or emotional factors, the three strands of the NS integrate the stimulus information to generate a GI effector response and cause pain sensation. Appropriate execution of this process depends on the structural integrity and electrophysiological properties of the intestinal neurons involved, which are in turn controlled by the SCF/c-Kit axis: SCF is constitutively expressed in various regions of the NS including the CNS, ENS and ANS, but specific expression levels are influenced by external stimuli (54). SCF directly affects neurotransmission by binding its receptor c-Kit and this influences the efficacy of the NS response to external stimuli (12). Indeed, experimental studies in a depression mouse model revealed a correlation between decreased c-Kit expression in the hippocampus and impaired neuronal differentiation and migration (55). It is well established that severe depression is a key factor predisposing to IBS development (56,57). Therefore, a relationship between altered SCF/c-Kit signals with the emotional, psychological and physical stimulated state of IBS patients is possible (58). Potential effector mechanisms may depend on SCF/c-Kit-mediated effects on the phosphorylation status of receptor systems involved in sensing neurotransmitter levels, including the neuronal nitric oxide synthase (nNOS), SP, NK1 and TRPV1 systems (59,60). This has been shown to result in overstimulation of the nerve-ICC-smooth muscle signal transfer system, promoting development of IBS-like symptoms (61). Similarly, in experimental IBS, changes in the regulation of SCF/c-Kit may stimulate strong nerve reflexes and enhance the rhythm of smooth muscle contraction, while simultaneously stimulating pain perception (14,62). However, the contributions of such activity to clinical IBS remains to be established.

SCF/c-Kit axis and abnormalities of the endocrine system

It is well established that malfunction of the brain-gut axis is a key mechanism in explaining IBS pathogenesis (63). In addition to direct innervation between the brain and the gut, it is often assumed that the endocrine system is an important connection between the two systems. Indeed, there is an established link between disturbed serum hormone levels and IBS (60,64), due to hormone secretion typically being related to the psychological state of the patient. This may explain IBS-related stress and other psychological disorders. Relevant mediators include 5-HT, nerve peptide Y, calcitonin gene-related peptide and histamine (65,66). The secretion of these is altered by the patient's psychological state, with the secreted factors targeting the intestinal ICC network. The SCF/c-Kit axis may facilitate the perception of such endocrinological signals, as it has been found that stimulation of c-Kit provokes substantial leukotriene C4 release via the activation of cytosolic phospholipase A2 (67). This is then associated with increased affinity of histamine and 5HT receptors for their ligands (68,69). As such, the SCF/c-Kit axis promotes sensitivity to GI hormones and thus may have a detrimental influence on pain perception, inflammation and bowel movement.

SCF/c-Kit and the immune system

Low-grade intestinal inflammation is established as a key characteristic of IBS (70,71) and is related to MC activation, as well as altered permeability of the intestinal mucosa to antigens (71,72). The general principal genomic regulator of the inflammatory response is nuclear factor-κB (NF-κB). Inactive NF-κB is sequestered in the cytoplasm, while activated NF-κB enters the nucleus and stimulates transcription of a range of proinflammatory factors, including tumor necrosis factor-α (TNF-α) and interleukin-1β. C-kit may activate NF-κB and promote the release of TNF-α when it is sensitized, which may be one way of SCF/C-kit initiating the immune inflammatory response (51,73). In addition, the trophic action of SCF/c-Kit on the MC compartment is directly associated with diarrhea-predominant IBS. Furthermore, c-Kit-mediated cysteinyl production results in sensitization of MC receptors involved in secretion of proinflammatory mediators, in turn enhancing the inflammatory response. These findings demonstrate a mild inflammatory response is stimulated through SCF/c-Kit signaling, which potentially links to IBS pathogenesis.

SCF/c-Kit and visceral hypersensitivity in IBS

Zhang et al developed an IBS rat model via infection with Trichinella spiralis (74). Rat models are generally not appropriate targets for genetic intervention, however, imatinib mesylate (STI-571), a moderately specific blocker of c-Kit (75), is amenable to experimental investigation in this model. A previous study revealed that the change of intestinal ICC activator rectus muscle electricity and dorsal commissural nucleus (DCN) were higher in the IBS rat, compared with the other rat model, whereas they decreased significantly following STI-571 exposure. It was indicated that visceral hypersensitivity in IBS rats may be suppressed when blocked the SCF/C-kit signal (74). These results indicate the importance of the SCF/c-Kit axis in IBS and the pharmacological implications of this axis, with imatinib offering a potential therapeutic option for targeting visceral hypersensitivity.

Visceral hypersensitivity is a key characteristic of IBS. The strong dependence of IBS-related pain on psychological and environmental conditions indicates that the pain is under CNS control, however, activity and sensitivity of the spinal sensory nerve fibers may additionally be dependent on endocrinological control (9,10). In this instance, the neurotrophic action of SCF may directly affect and stimulate neurotransmitter responses via the SCF-c-Kit axis (12). In the ENS, periodic slow wave potentials between the ICC and SMCs are generated and perceived by neurotransmitter receptors, including those for SP, vasoactive intestinal peptide, histamine, serotonin and acetylcholine, expressed on the ICC membranes. In turn, these receptors mediate contractile and relaxant effects in GI smooth muscle and pain perception (76). As stated above, MCs may further amplify the pain signals (77), though the pain threshold itself appears largely dependent on the activation state of the SCF/c-Kit axis. Small intestinal resection and transmission microscopy observations indicate that modifying the c-Kit pathway or activating the SCF/c-Kit pathway affects the depolarization and pacemaker functions of the ICC and alters intestinal rhythm (78). However, whether clinical trials employing imatinib provide benefit for these effects is unclear and warrants further study.

Conclusion

IBS is a functional disease associated with multiple systems in the body, though it is particularly associated with brain-gut cross-talk via modulation of the endocrine system. The results of this include aberrant GI motility and visceral hypersensitivity, in turn leading to abdominal discomfort and abnormal defecation patterns. The SCF/c-Kit signaling system is critical in controlling many of the elements involved (Fig. 2), including ICC MC and nerve cells, and thus shows potential as a pharmacological, intervention aimed at combatting visceral sensitivity and GI disorder in IBS patients. The ICC serve as the pacemakers for GI smooth muscle contraction and integrate neuroendocrine physiology (72). ICCs depend on SCF/c-Kit interaction for growth and development and respond to its signaling by upregulating neurotransmission. Pain perception in ICCs is increased through the effects of SCF/c-Kit on MCs. Fortunately, pharmacological antagonists for SFC/c-Kit signaling are clinically available. For instance, inhibitors including imatinib, sorafenib, lapatinib and sunitinib are capable at a minimum of partially targeting this signaling system (7375). In addition, imatinib is reasonably c-Kit-specific, however the physiological importance of SCF/c-Kit signal transduction in nearly all cell types derived from the neuronal crest lineage may prevent the use of inhibitory strategies. As a factor involved in GI motility, visceral sensitivity and inflammatory signaling, blockade of SCF/c-Kit may trigger collateral damage, which would likely preclude its use in a non-lethal disease such as IBS (76,77). Therefore, further studies with animal models are required to develop acceptable interventions. In addition, further insight is required into the mechanisms mediating SCF/c-Kit signaling. Design of new drugs specifically inhibiting SCF/c-Kit signal transduction, that preferentially act locally in the intestine, may be critical for successful outcomes. Such targeting of SCF/c-Kit inhibition is a novel strategy in IBS therapy.

Acknowledgements

This study was supported by the Guangdong province Nature Science Foundation of China (grant no. 2014A030313404), the Natural Science Foundation of China (grant no. 81673842) and the ‘Excellent Doctoral Dissertation Incubation Grant’ from the First Clinical School of Guangzhou University of Chinese Medicine (grant no. YB201402).

Glossary

Abbreviations

Abbreviations:

IBS

irritable bowel syndrome

SCF

stem cell factor

ICC

intestinal cells of Cajal

RTK

receptor tyrosine kinase

GI

gastrointestinal

SMC

smooth muscle cell

Src

a tyrosine-protein kinase

SP

substance P

NK1

neurokinin-1

TRPV

transient receptor potential vanilloid

5-HT

5-hydroxytryptamine

MC

mast cell

NC

nerve cell

NS

nervous system

ENS

enteric nervous system

ANS

autonomic nervous system

CNS

central nervous system

NF-κB

nuclear factor-κB

TNF-α

tumor necrosis factor-α

References

1 

Chassany O, Bonaz B, Bruley DES, Varannes S, Bueno L, Cargill G, Coffin B, Ducrotté P and Grangé V: Acute exacerbation of pain in irritable bowel syndrome: Efficacy of phloroglucinol/trimethylphloroglucinol. A randomized, double-blind, placebo-controlled study. Aliment Pharmacol Ther. 25:1115–1123. 2007. View Article : Google Scholar : PubMed/NCBI

2 

Horwitz BJ and Fisher RS: The irritable bowel syndrome. N Engl J Med. 344:1846–1850. 2001. View Article : Google Scholar : PubMed/NCBI

3 

Moghimi-Dehkordi B, Vahedi M, Pourhoseingholi MA, Mansoori B Khoshkrood, Safaee A, Habibi M, Pourhoseingholi A and Zali MR: Economic burden attributable to functional bowel disorders in Iran: A cross-sectional population-based study. J Dig Dis. 12:384–392. 2011. View Article : Google Scholar : PubMed/NCBI

4 

Schonrich S, Brockow T, Franke T, Dembski R, Resch KL and Cieza A: Analyzing the content of outcome measures in clinical trials on irritable bowel syndrome using the international classification of functioning, disability and health as a reference. Rehabilitation (Stuttg). 45:172–180. 2006. View Article : Google Scholar : PubMed/NCBI

5 

Spinelli A: Irritable bowel syndrome. Clin Drug Investig. 27:15–33. 2007. View Article : Google Scholar : PubMed/NCBI

6 

Chey WD, Kurlander J and Eswaran S: Irritable bowel syndrome: A clinical review. JAMA. 313:949–958. 2015. View Article : Google Scholar : PubMed/NCBI

7 

Konstantinov SR and Peppelenbosch MP: Fecal microbiota transfer may increase irritable bowel syndrome and inflammatory bowel diseases-associated bacteria. Gastroenterology. 144:e19–e20. 2013. View Article : Google Scholar : PubMed/NCBI

8 

Saha L: Irritable bowel syndrome: Pathogenesis, diagnosis, treatment, and evidence-based medicine. World J Gastroenterol. 20:6759–6773. 2014. View Article : Google Scholar : PubMed/NCBI

9 

Bajwa SJ and Haldar R: Endocrinological disorders affecting neurosurgical patients: An intensivists perspective. Indian J Endocrinol Metab. 18:778–783. 2014. View Article : Google Scholar : PubMed/NCBI

10 

Baldinger P, Kranz G, Höflich A, Savli M, Stein P, Lanzenberger R and Kasper S: The effects of hormone replacement therapy on mind and brain. Nervenarzt. 84:14–19. 2013.(in German). View Article : Google Scholar : PubMed/NCBI

11 

Yang J, Shi YQ and Zhao XY: Expression and significance of SCF and 5-HT in the intestinal mucosa of patients with diarrhea predominant irritable bowel syndrome. Jilin Medicine. 4:646–647. 2015.

12 

Sun YG, Gracias NG, Drobish JK, Vasko MR, Gereau RW and Chen ZF: The c-kit signaling pathway is involved in the development of persistent pain. Pain. 144:178–186. 2009. View Article : Google Scholar : PubMed/NCBI

13 

Jin QH, Shen HX, Wang H, Shou QY and Liu Q: Curcumin improves expression of SCF/c-kit through attenuating oxidative stress and NF-κB activation in gastric tissues of diabetic gastroparesis rats. Diabetol Metab Syndr. 5:122013. View Article : Google Scholar : PubMed/NCBI

14 

Liu G, Chen ZY, Ma L, Lou X, Li SJ and Wang YL: Intracranial hemangiopericytoma: MR imaging findings and diagnostic usefulness of minimum ADC values. J Magn Reson Imaging. 38:1146–1151. 2013. View Article : Google Scholar : PubMed/NCBI

15 

Eshraghian A and Eshraghian H: Interstitial cells of Cajal: A novel hypothesis for the pathophysiology of irritable bowel syndrome. Can J Gastroenterol. 25:277–279. 2011. View Article : Google Scholar : PubMed/NCBI

16 

Zhou YL, Zhang W, Gao EL, Dai XX, Yang H, Zhang XH and Wang OC: Preoperative BRAF mutation is predictive of occult contralateral carcinoma in patients with unilateral papillary thyroid microcarcinoma. Asian Pac J Cancer Prev. 13:1267–1272. 2012. View Article : Google Scholar : PubMed/NCBI

17 

Feng ZC, Riopel M, Popell A and Wang R: A survival Kit for pancreatic beta cells: Stem cell factor and c-Kit receptor tyrosine kinase. Diabetologia. 58:654–665. 2015. View Article : Google Scholar : PubMed/NCBI

18 

Edling CE and Hallberg B: c-Kit-a hematopoietic cell essential receptor tyrosine kinase. Int J Biochem Cell Biol. 39:1995–1998. 2007. View Article : Google Scholar : PubMed/NCBI

19 

Tamada H and Kiyama H: Existence of c-Kit negative cells with ultrastructural features of interstitial cells of Cajal in the subserosal layer of the W/Wv mutant mouse colon. J Smooth Muscle Res. 51:1–9. 2015. View Article : Google Scholar

20 

Morimoto M: Intestinal smooth muscle cells locally enhance stem cell factor (SCF) production against gastrointestinal nematode infections. J Vet Med Sci. 73:805–807. 2011. View Article : Google Scholar : PubMed/NCBI

21 

Ali S and Ali S: Role of c-kit/SCF in cause and treatment of gastrointestinal stromal tumors (GIST). Gene. 401:38–45. 2007. View Article : Google Scholar : PubMed/NCBI

22 

Liang J, Wu YL, Chen BJ, Zhang W, Tanaka Y and Sugiyama H: The C-kit receptor-mediated signal transduction and tumor-related diseases. Int J Biol Sci. 9:435–443. 2013. View Article : Google Scholar : PubMed/NCBI

23 

Tong W, Jia H, Zhang L, Li C, Ridolfi TJ and Liu B: Exogenous stem cell factor improves interstitial cells of Cajal restoration after blockade of c-kit signaling pathway. Scand J Gastroenterol. 45:844–851. 2010. View Article : Google Scholar : PubMed/NCBI

24 

Tan YY, Ji ZL, Zhao G, Jiang JR, Wang D and Wang JM: Decreased SCF/c-kit signaling pathway contributes to loss of interstitial cells of Cajal in gallstone disease. Int J Clin Exp Med. 7:4099–4106. 2014.PubMed/NCBI

25 

Das Roy L, Curry JM, Sahraei M, Besmer DM, Kidiyoor A, Gruber HE and Mukherjee P: Arthritis augments breast cancer metastasis: Role of mast cells and SCF/c-Kit signaling. Breast Cancer Res. 15:R322013. View Article : Google Scholar : PubMed/NCBI

26 

Reber L, Da Silva CA and Frossard N: Stem cell factor and its receptor c-Kit as targets for inflammatory diseases. Eur J Pharmacol. 533:327–340. 2006. View Article : Google Scholar : PubMed/NCBI

27 

Okayama Y and Kawakami T: Development, migration, and survival of mast cells. Immunol Res. 34:97–115. 2006. View Article : Google Scholar : PubMed/NCBI

28 

Bos CL, Richel DJ, Ritsema T, Peppelenbosch MP and Versteeg HH: Prostanoids and prostanoid receptors in signal transduction. Int J Biochem Cell Biol. 36:1187–1205. 2004. View Article : Google Scholar : PubMed/NCBI

29 

Movat HZ: The role of histamine and other mediators in microvascular changes in acute inflammation. Can J Physiol Pharmacol. 65:451–457. 1987. View Article : Google Scholar : PubMed/NCBI

30 

Magierowski M, Jasnos K, Kwiecien S, Drozdowicz D, Surmiak M, Strzalka M, Ptak-Belowska A, Wallace JL and Brzozowski T: Endogenous prostaglandins and afferent sensory nerves in gastroprotective effect of hydrogen sulfide against stress-induced gastric lesions. PLoS One. 10:e01189722015. View Article : Google Scholar : PubMed/NCBI

31 

Di Gennaro A and Haeggström JZ: The leukotrienes: Immune-modulating lipid mediators of disease. Adv Immunol. 116:51–92. 2012. View Article : Google Scholar : PubMed/NCBI

32 

Huizinga JD, Robinson TL and Thomsen L: The search for the origin of rhythmicity in intestinal contraction; from tissue to single cells. Neurogastroenterol Motil. 12:3–9. 2000. View Article : Google Scholar : PubMed/NCBI

33 

Jee SR, Morales W, Low K, Chang C, Zhu A, Pokkunuri V, Chatterjee S, Soffer E, Conklin JL and Pimentel M: ICC density predicts bacterial overgrowth in a rat model of post-infectious IBS. World J Gastroenterol. 16:3680–3686. 2010. View Article : Google Scholar : PubMed/NCBI

34 

Burns AJ, Herbert TM, Ward SM and Sanders KM: Interstitial cells of Cajal in the guinea-pig gastrointestinal tract as revealed by c-Kit immunohistochemistry. Cell Tissue Res. 290:11–20. 1997. View Article : Google Scholar : PubMed/NCBI

35 

Blair PJ, Bayguinov Y, Sanders KM and Ward SM: Interstitial cells in the primate gastrointestinal tract. Cell Tissue Res. 350:199–213. 2012. View Article : Google Scholar : PubMed/NCBI

36 

Mitsui R and Komuro T: Distribution and ultrastructure of interstitial cells of Cajal in the gastric antrum of wild-type and Ws/Ws rats. Anat Embryol (Berl). 206:453–460. 2003. View Article : Google Scholar : PubMed/NCBI

37 

Miyamoto-Kikuta S, Ezaki T and Komuro T: Distribution and morphological characteristics of the interstitial cells of Cajal in the ileocaecal junction of the guinea-pig. Cell Tissue Res. 338:29–35. 2009. View Article : Google Scholar : PubMed/NCBI

38 

Gao J, Du P, O'Grady G, Archer R, Gibbons SJ, Farrugia G and Cheng LK: Cellular automaton model for simulating tissue-specific intestinal electrophysiological activity. Conf Proc IEEE Eng Med Biol Soc. 2013:5537–5540. 2013.PubMed/NCBI

39 

Bassotti G and Villanacci V: Colonic diverticular disease: Abnormalities of neuromuscular function. Dig Dis. 30:24–28. 2012. View Article : Google Scholar : PubMed/NCBI

40 

Huang X and Xu WX: The pacemaker functions of visceral interstitial cells of Cajal. Sheng Li Xue Bao. 62:387–397. 2010.PubMed/NCBI

41 

Shin DH, Lee MJ, Jiao HY, Choi S, Kim MW, Park CG, Na J, Kim SW, Park IK, So I and Jun JY: Regulatory roles of endogenous mitogen-activated protein kinases and tyrosine kinases in the pacemaker activity of colonic interstitial cells of cajal. Pharmacology. 96:16–24. 2015. View Article : Google Scholar : PubMed/NCBI

42 

Sohn W, Lee OY, Lee SP, Lee KN, Jun DW, Lee HL, Yoon BC, Choi HS, Sim J and Jang KS: Mast cell number, substance P and vasoactive intestinal peptide in irritable bowel syndrome with diarrhea. Scand J Gastroenterol. 49:43–51. 2014. View Article : Google Scholar : PubMed/NCBI

43 

Braak B, Klooker TK, Wouters MM, Welting O, van der Loos CM, Stanisor OI, van Diest S, van den Wijngaard RM and Boeckxstaens GE: Mucosal immune cell numbers and visceral sensitivity in patients with irritable bowel syndrome: Is there any relationship? Am J Gastroenterol. 107:715–726. 2012. View Article : Google Scholar : PubMed/NCBI

44 

Tsang CM, Wong CK, Ip WK and Lam CW: Synergistic effect of SCF and TNF-alpha on the up-regulation of cell-surface expression of ICAM-1 on human leukemic mast cell line (HMC)-1 cells. J Leukoc Biol. 78:239–247. 2005. View Article : Google Scholar : PubMed/NCBI

45 

Draber P, Halova I, Polakovicova I and Kawakami T: Signal transduction and chemotaxis in mast cells. Eur J Pharmacol. 778:11–23. 2016. View Article : Google Scholar : PubMed/NCBI

46 

Collmann E, Bohnacker T, Marone R, Dawson J, Rehberg M, Stringer R, Krombach F, Burkhart C, Hirsch E, Hollingworth GJ, et al: Transient targeting of phosphoinositide 3-kinase acts as a roadblock in mast cells' route to allergy. J Allergy Clin Immunol. 132:959–968. 2013. View Article : Google Scholar : PubMed/NCBI

47 

Kojima T, Hirota Y, Ema M, Takahashi S, Miyoshi I, Okano H and Sawamoto K: Subventricular zone-derived neural progenitor cells migrate along a blood vessel scaffold toward the post-stroke striatum. Stem Cells. 28:545–554. 2010.PubMed/NCBI

48 

Jin K, Mao XO, Sun Y, Xie L and Greenberg DA: Stem cell factor stimulates neurogenesis in vitroin vivo. J Clin Invest. 110:311–319. 2002. View Article : Google Scholar : PubMed/NCBI

49 

Drăghici IM, Drăghici L, Cojocaru M, Gorgan CL and Vrabie CD: The immunoprofile of interstitial Cajal cells within adenomyosis/endometriosis lesions. Rom J Morphol Embryol. 56:133–138. 2015.PubMed/NCBI

50 

Lu T, Luo Y, Sun H, Qin W and Li Y: Electroacupuncture improves behavioral recovery and increases SCF/c-kit expression in a rat model of focal cerebral ischemia/reperfusion. Neurol Sci. 34:487–495. 2013. View Article : Google Scholar : PubMed/NCBI

51 

Micheva-Viteva SN, Shou Y, Nowak-Lovato KL, Rector KD and Hong-Geller E: c-KIT signaling is targeted by pathogenic Yersinia to suppress the host immune response. BMC Microbiol. 13:2492013. View Article : Google Scholar : PubMed/NCBI

52 

Guo S, Tao X, Wang Y, Tang J, Shen L and Song C: SCF/c-Kit signaling promotes invasion of T24 cells via PI3K pathway. Nan Fang Yi Ke Da Xue Xue Bao. 34:507–510. 2014.(In Chinese). PubMed/NCBI

53 

Zheng Z and Tang H: Decreased neuroplasticity may play a role in irritable bowel syndrome: Implication from the comorbidity of depression and irritable bowel syndrome. J Neurogastroenterol Motil. 21:298–299. 2015. View Article : Google Scholar : PubMed/NCBI

54 

Da Silva CA, Reber L and Frossard N: Stem cell factor expression, mast cells and inflammation in asthma. Fundam Clin Pharmacol. 20:21–39. 2006. View Article : Google Scholar : PubMed/NCBI

55 

Xiao Y: SCF/c-Kit signaling acts as a new etiologic factor of depression by regulation adult neurogenesis. PhD dissertationShanghai Jiaotong University China: 2010

56 

Keightley P, Pavli P, Platten J and Looi JC: Gut feelings 1. Mind, mood and gut in irritable bowel syndrome: Approaches to psychiatric care. Australas Psychiatry. 23:403–406. 2015. View Article : Google Scholar : PubMed/NCBI

57 

Muscatello MR, Bruno A, Scimeca G, Pandolfo G and Zoccali RA: Role of negative affects in pathophysiology and clinical expression of irritable bowel syndrome. World J Gastroenterol. 20:7570–7586. 2014. View Article : Google Scholar : PubMed/NCBI

58 

Guo XZ: SCF/c-Kit signaling acts as a new etiological factor of depression by regulating adult hippocampal neurogenesis. In: Proceedings of the Chinese society of genetic model organisms and human health conference. 2010

59 

Zhao X, Suo HY, Qian Y, Li GJ, Liu ZH and Li J: Therapeutic effects of Lactobacillus casei Qian treatment in activated carbon-induced constipated mice. Mol Med Rep. 12:3191–3199. 2015.PubMed/NCBI

60 

Matsumoto K, Hosoya T, Tashima K, Namiki T, Murayama T and Horie S: Distribution of transient receptor potential vanilloid 1 channel-expressing nerve fibers in mouse rectal and colonic enteric nervous system: Relationship to peptidergic and nitrergic neurons. Neuroscience. 172:518–534. 2011. View Article : Google Scholar : PubMed/NCBI

61 

DiNitto JP, Deshmukh GD, Zhang Y, Jacques SL, Coli R, Worrall JW, Diehl W, English JM and Wu JC: Function of activation loop tyrosine phosphorylation in the mechanism of c-Kit auto-activation and its implication in sunitinib resistance. J Biochem. 147:601–609. 2010. View Article : Google Scholar : PubMed/NCBI

62 

Yamamoto T, Watabe K, Nakahara M, Ogiyama H, Kiyohara T, Tsutsui S, Tamura S, Shinomura Y and Hayashi N: Disturbed gastrointestinal motility and decreased interstitial cells of Cajal in diabetic db/db mice. J Gastroenterol Hepatol. 23:660–667. 2008. View Article : Google Scholar : PubMed/NCBI

63 

Okumura T: Brain-gut interaction in the pathophysiology of IBS. Nihon Shokakibyo Gakkai Zasshi. 111:1334–1344. 2014.(In Japanese). PubMed/NCBI

64 

Keszthelyi D, Troost FJ, Jonkers DM, van Eijk HM, Dekker J, Buurman WA and Masclee AA: Visceral hypersensitivity in irritable bowel syndrome: Evidence for involvement of serotonin metabolism-a preliminary study. Neurogastroenterol Motil. 27:1127–1137. 2015. View Article : Google Scholar : PubMed/NCBI

65 

Sun J, Wu X, Meng Y, Cheng J, Ning H, Peng Y, Pei L and Zhang W: Electro-acupuncture decreases 5-HT, CGRP and increases NPY in the brain-gut axis in two rat models of Diarrhea-predominant irritable bowel syndrome(D-IBS). BMC Complement Altern Med. 15:3402015. View Article : Google Scholar : PubMed/NCBI

66 

Camilleri M, Oduyebo I and Halawi H: Chemical and molecular factors in irritable bowel syndrome: Current knowledge, challenges, and unanswered questions. Am J Physiol Gastrointest Liver Physiol. 311:G777–G784. 2016. View Article : Google Scholar : PubMed/NCBI

67 

Murakami M, Austen KF and Arm JP: The immediate phase of c-kit ligand stimulation of mouse bone marrow-derived mast cells elicits rapid leukotriene C4 generation through posttranslational activation of cytosolic phospholipase A2 and 5-lipoxygenase. J Exp Med. 182:197–206. 1995. View Article : Google Scholar : PubMed/NCBI

68 

Pynaert G, Grooten J, van Deventer SJ and Peppelenbosch MP: Cysteinyl leukotrienes mediate histamine hypersensitivity ex vivo by increasing histamine receptor numbers. Mol Med. 5:685–692. 1999.PubMed/NCBI

69 

Bloemers SM, Verheule S, Peppelenbosch MP, Smit MJ, Tertoolen LG and de Laat S: Sensitization of the histamine H1 receptor by increased ligand affinity. J Biol Chem. 273:2249–2255. 1998. View Article : Google Scholar : PubMed/NCBI

70 

Martínez C, Lobo B, Pigrau M, Ramos L, González-Castro AM, Alonso C, Guilarte M, Guilá M, de Torres I, Azpiroz F, et al: Diarrhoea-predominant irritable bowel syndrome: An organic disorder with structural abnormalities in the jejunal epithelial barrier. GUT. 62:1160–1168. 2013. View Article : Google Scholar : PubMed/NCBI

71 

Vicario M, González-Castro AM, Martinez C, Lobo B, Pigrau M, Guilarte M, de Torres I, Mosquera JL, Fortea M, Sevillano-Aguilera C, et al: Increased humoral immunity in the jejunum of diarrhoea-predominant irritable bowel syndrome associated with clinical manifestations. GUT. 64:1379–1388. 2015. View Article : Google Scholar : PubMed/NCBI

72 

Willot S, Gauthier C, Patey N and Faure C: Nerve growth factor content is increased in the rectal mucosa of children with diarrhea-predominant irritable bowel syndrome. Neurogastroenterol Motil. 24:734–739, e347. 2012. View Article : Google Scholar : PubMed/NCBI

73 

Eby JM, Kang HK, Klarquist J, Chatterjee S, Mosenson JA, Nishimura MI, Garrett-Mayer E, Longley BJ, Engelhard VH, Mehrotra S and Le Poole IC: Immune responses in a mouse model of vitiligo with spontaneous epidermal de- and repigmentation. Pigment Cell Melanoma Res. 27:1075–1085. 2014. View Article : Google Scholar : PubMed/NCBI

74 

Zhang JY, Huang YX, Qin M and Wang JJ: Effect of overactivation of stem cell factor/c-kit on hyperalgesia in rats with irritable bowel syndrome. Journal of Shangxi Medical University. 3:177–181. 2012.

75 

Siehl J and Thiel E: C-kit, GIST, and imatinib. Recent Results Cancer Res. 176:145–151. 2007. View Article : Google Scholar : PubMed/NCBI

76 

D'Antonio C, Wang B, McKay C and Huizinga JD: Substance P activates a non-selective cation channel in murine pacemaker ICC. Neurogastroenterol Motil. 21:e979–985. 2009.

77 

Milenkovic N, Frahm C, Gassmann M, Griffel C, Erdmann B, Birchmeier C, Lewin GR and Garratt AN: Nociceptive tuning by stem cell factor/c-Kit signaling. Neuron. 56:893–906. 2007. View Article : Google Scholar : PubMed/NCBI

78 

Chen J, Du L, Xiao YT and Cai W: Disruption of interstitial cells of Cajal networks after massive small bowel resection. World J Gastroenterol. 19:3415–3422. 2013. View Article : Google Scholar : PubMed/NCBI

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April 2017
Volume 13 Issue 4

Print ISSN: 1792-0981
Online ISSN:1792-1015

2015 Impact Factor: 1.28
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APA
Chai, Y., Huang, Y., Tang, H., Tu, X., He, J., Wang, T. ... Qiu, Z. (2017). Role of stem cell growth factor/c-Kit in the pathogenesis of irritable bowel syndrome (Review). Experimental and Therapeutic Medicine, 13, 1187-1193. https://doi.org/10.3892/etm.2017.4133
MLA
Chai, Y., Huang, Y., Tang, H., Tu, X., He, J., Wang, T., Zhang, Q., Xiong, F., Li, D., Qiu, Z."Role of stem cell growth factor/c-Kit in the pathogenesis of irritable bowel syndrome (Review)". Experimental and Therapeutic Medicine 13.4 (2017): 1187-1193.
Chicago
Chai, Y., Huang, Y., Tang, H., Tu, X., He, J., Wang, T., Zhang, Q., Xiong, F., Li, D., Qiu, Z."Role of stem cell growth factor/c-Kit in the pathogenesis of irritable bowel syndrome (Review)". Experimental and Therapeutic Medicine 13, no. 4 (2017): 1187-1193. https://doi.org/10.3892/etm.2017.4133