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Means SA, Hussan JR, Garrett AS, Cheng LK, Clark AR. Electrical wave generation and spatial organization in uterine tissue. J R Soc Interface 2025; 22:20240638. [PMID: 40364760 PMCID: PMC12076165 DOI: 10.1098/rsif.2024.0638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Revised: 12/03/2024] [Accepted: 01/31/2025] [Indexed: 05/15/2025] Open
Abstract
Healthy uterine function requires coordinated and spatially organized contractions over the menstrual cycle (oestrus in animals) and at term in pregnancy. The underlying mechanisms triggering and coordinating uterine contractions, without a distinct pacemaking region, are poorly understood. Potentially, gap-junction coupling between excitable smooth muscle cells themselves or between electrically passive cells (telocytes or fibroblasts) and excitable cells may be key. Here, we present a lattice-tissue model of coupled excitable and passive cells to investigate a potential mechanism of coordinated tissue contraction. Bifurcation analysis of cell pairs quantifies parameter windows exhibiting oscillatory behaviour. Within these windows, we demonstrate conditions when the magnitude and spatial distribution of coupling strengths generate electrical waves. Energy-based analysis of excitable cells provides quantification of intercellular energy differences cells required for spontaneous wave generation. Our model suggests passive cells must rest at a membrane voltage sufficiently higher than smooth muscle cells to trigger activity and that coupling between excitable and passive cells in spatially concentrated regions could influence the direction of tissue-wide electrical waves. This suggests that both the total number of gap junctions and their spatial expression may play a role in coordinating uterine contractility.
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Affiliation(s)
- Shawn A. Means
- Auckland Bioengineering Institute, University of Auckland, Auckland, New Zealand
| | - Jagir R. Hussan
- Auckland Bioengineering Institute, University of Auckland, Auckland, New Zealand
| | - Amy S. Garrett
- Auckland Bioengineering Institute, University of Auckland, Auckland, New Zealand
| | - Leo K. Cheng
- Auckland Bioengineering Institute, University of Auckland, Auckland, New Zealand
| | - Alys Rachel Clark
- Auckland Bioengineering Institute, University of Auckland, Auckland, New Zealand
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Li J, Fu Y, Wang Y, Zheng Y, Zhang K, Li Y. Qi Lang formula relieves constipation via targeting SCF/c-kit signaling pathway: An integrated study of network pharmacology and experimental validation. Heliyon 2024; 10:e31860. [PMID: 38841509 PMCID: PMC11152960 DOI: 10.1016/j.heliyon.2024.e31860] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Revised: 05/21/2024] [Accepted: 05/22/2024] [Indexed: 06/07/2024] Open
Abstract
Background Constipation is one of the chronic gastrointestinal functional diseases that affects the quality of life. While Qi Lang Formula (QLF) has demonstrated effectiveness in alleviating constipation symptoms, its precise mechanism remains elusive. Methods QLF was analyzed using UPLC-MS/MS. Targets for QLF were collected from SwissADME, Herb, ITCM databases, and constipation-related targets from scRNA-seq and Genecards databases. Overlapping targets suggested potential QLF therapy targets for constipation. Enrichment analysis used the KOBAS database. A "drug-ingredient-target" network was constructed with Cytoscape, and AutoDock verified active ingredient binding. H&E staining assessed colonic mucosa changes, TEM examined ICC structural changes. ELISA measured neurotransmitter levels, and Western blot verified QLF's effect on target proteins. ICC proliferation was observed through immunofluorescence. Results We identified 89 targets of QLF associated with ICC-related constipation, with c-Kit emerging as the pivotal target. Molecular docking studies revealed that Atractylenolide Ⅲ, Apigenin, Formononetin, Isorhamnetin, Naringenin, and Ononin exhibited strong binding affinities for the c-Kit structural domain. QLF significantly enhanced first stool passage time, fecal frequency, fecal moisture content, and intestinal propulsion rate. Further analysis unveiled that QLF not only restored neurotransmitter levels but also mitigated colon muscular fiber ruptures. ICC ultrastructure exhibited partial recovery, while Western blot confirmed upregulated c-Kit expression and downstream targets. Immunofluorescence results indicated ICC proliferation post QLF treatment in rat colon. Conclusion Our findings suggest that QLF may promote ICC proliferation by targeting SCF/c-Kit and its downstream signaling pathway, thereby regulating intestinal motility.
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Affiliation(s)
- Jiacheng Li
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China
- Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China
| | - Yugang Fu
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China
- Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China
| | - Yanping Wang
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China
- Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China
| | - Yiyuan Zheng
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China
| | - Kehui Zhang
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China
| | - Yong Li
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China
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Hendry ET, Balfe JG, Du P, Cakmak YO. Frequency-Specific Effects of Noninvasive Median Nerve Stimulation on Gastric Slow Wave Activity in Humans. Neuromodulation 2024:S1094-7159(24)00028-X. [PMID: 38466259 DOI: 10.1016/j.neurom.2023.12.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 12/08/2023] [Accepted: 12/31/2023] [Indexed: 03/12/2024]
Abstract
OBJECTIVES The present study explored the effects of different frequencies of noninvasive median nerve stimulation (nMNS) on two autonomic responses: gastric slow waves under water-loading condition and heart rate variability (HRV). To the best of our knowledge, this is the first study to document the effects of different frequencies of nMNS on gastric slow waves (GSW) in humans under 5-minute water-loading condition. MATERIALS AND METHODS Twenty healthy adult participants were fitted with a noninvasive body-surface gastric mapping, electrocardiogram (ECG), and a transcutaneous electrical nerve stimulation device and administered with four different nMNS frequencies (placebo-0 Hz, 40 Hz, 120 Hz, and 200 Hz) on four separate counterbalanced days. After the baseline and stimulation periods, a 5-minute water-load test was applied, and a post-water-load period also is recorded for ECG and GSW activity. Time-domain HRV parameters are analyzed with repeated-measures one-way analysis of variance (ANOVA) and a post hoc Tukey multiple comparison test. Parameters that failed normality tests underwent a Freidman test with a post hoc Dunn multiple comparison test. GSW data are analyzed with repeated-measures mixed-effects ANOVA. RESULTS In empty stomach (baseline vs stimulation), only the 40-Hz frequency statistically significantly (p = 0.0129) increased GSW amplitude in comparison with its own baseline. In full (distended) stomach, 40-Hz and 200-Hz stimulations showed a statistically significant difference (post hoc multiple comparison adjusted, p = 0.0016 and p = 0.0183, respectively) in the Gastric Rhythm Index in comparison with the change obtained by placebo stimulation (baseline vs poststimulation periods); 120-Hz nMNS showed a statistically significant difference (p = 0.0300) in the stress index in comparison with the decrease observed in the placebo group. However, 120-Hz nMNS did not induce a statistically significant change in gastric electrical activity compared to placebo stimulation. The nMNS did not follow the linear "dose-response" relationship between nMNS frequency and gastric/HRV parameters. CONCLUSIONS The 40-Hz and 200-Hz nMNS frequencies showed the most promising results in response to gastric distension, in addition to 40 Hz for an empty stomach. Further research is essential to explore the potential therapeutic effects of these frequencies on gastric diseases such as gastroparesis, gastroesophageal reflux disease, and functional dyspepsia that can be used in wrist wearables.
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Affiliation(s)
| | | | - Peng Du
- Auckland Bioengineering Institute, University of Auckland, Auckland, New Zealand
| | - Yusuf Ozgur Cakmak
- Cakmak Lab, Department of Anatomy, University of Otago, Dunedin, New Zealand; Center for Bioengineering-Point-of-Care Technologies, University of Otago, Dunedin, New Zealand; Medtech Core New Zealand-Interventional Technologies Theme, Auckland, New Zealand; Centre for Health Systems and Technology, University of Otago, Dunedin, New Zealand.
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López-Pingarrón L, Almeida H, Soria-Aznar M, Reyes-Gonzales MC, Rodríguez-Moratinos AB, Muñoz-Hoyos A, García JJ. Interstitial Cells of Cajal and Enteric Nervous System in Gastrointestinal and Neurological Pathology, Relation to Oxidative Stress. Curr Issues Mol Biol 2023; 45:3552-3572. [PMID: 37185756 PMCID: PMC10136929 DOI: 10.3390/cimb45040232] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Revised: 04/16/2023] [Accepted: 04/17/2023] [Indexed: 05/17/2023] Open
Abstract
The enteric nervous system (ENS) is organized into two plexuses-submucosal and myenteric-which regulate smooth muscle contraction, secretion, and blood flow along the gastrointestinal tract under the influence of the rest of the autonomic nervous system (ANS). Interstitial cells of Cajal (ICCs) are mainly located in the submucosa between the two muscle layers and at the intramuscular level. They communicate with neurons of the enteric nerve plexuses and smooth muscle fibers and generate slow waves that contribute to the control of gastrointestinal motility. They are also involved in enteric neurotransmission and exhibit mechanoreceptor activity. A close relationship appears to exist between oxidative stress and gastrointestinal diseases, in which ICCs can play a prominent role. Thus, gastrointestinal motility disorders in patients with neurological diseases may have a common ENS and central nervous system (CNS) nexus. In fact, the deleterious effects of free radicals could affect the fine interactions between ICCs and the ENS, as well as between the ENS and the CNS. In this review, we discuss possible disturbances in enteric neurotransmission and ICC function that may cause anomalous motility in the gut.
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Affiliation(s)
- Laura López-Pingarrón
- Department of Pharmacology, Physiology and Legal and Forensic Medicine, Faculty of Medicine, University of Zaragoza, 50009 Zaragoza, Spain
| | - Henrique Almeida
- i3S-Instituto de Investigação e Inovação em Saúde, Porto University, 4200-135 Porto, Portugal
- Department of Biomedicine, Faculty of Medicine, Porto University, 4200-319 Porto, Portugal
- Department of Obstetrics and Gynecology, Hospital-CUF Porto, 4100-180 Porto, Portugal
| | - Marisol Soria-Aznar
- Department of Pharmacology, Physiology and Legal and Forensic Medicine, Faculty of Medicine, University of Zaragoza, 50009 Zaragoza, Spain
| | - Marcos C Reyes-Gonzales
- Department of Pharmacology, Physiology and Legal and Forensic Medicine, Faculty of Medicine, University of Zaragoza, 50009 Zaragoza, Spain
| | | | - Antonio Muñoz-Hoyos
- Department of Pediatrics, Faculty of Medicine, University of Granada, 18016 Granada, Spain
| | - Joaquín J García
- Department of Pharmacology, Physiology and Legal and Forensic Medicine, Faculty of Medicine, University of Zaragoza, 50009 Zaragoza, Spain
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Klemm L, Seydewitz R, Siebert T, Böl M. Three-dimensional multi-field modelling of gastric arrhythmias and their effects on antral contractions. Comput Biol Med 2023; 153:106488. [PMID: 36592609 DOI: 10.1016/j.compbiomed.2022.106488] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 12/19/2022] [Accepted: 12/25/2022] [Indexed: 12/31/2022]
Abstract
The contraction activation of smooth muscle in the stomach wall (SW) is coordinated by slow electrical waves. The interstitial cells of Cajal (ICC), specialised pacemaker cells, initiate and propagate these slow waves. By establishing an electrically coupled network, each ICC adjusts its intrinsic pacing frequency to a single dominant frequency, to be a key aspect in modelling the electrophysiology of gastric tissue. In terms of modelling, additional fields associated with electrical activation, such as voltage-dependent calcium influx and the resulting deformation, have hardly been considered so far. Here we present a three-dimensional model of the electro-chemomechanical activation of gastric smooth muscle contractions. To reduce computational costs, an adaptive multi-scale discretisation strategy for the temporal resolution of the electric field is used. The model incorporates a biophysically based model of gastric ICC pacemaker activity that aims to simulate stable entrainment and physiological conduction velocities of the electrical slow waves. Together with the simulation of concomitant gastric contractions and the inclusion of a mechanical feedback mechanism, the model is used to study dysrhythmias of gastric slow waves induced by abnormal stretching of the antral SW. The model is able to predict the formation of stretch-induced gastric arrhythmias, such as the emergence of an ectopic pacemaker in the gastric antrum. The results show that the ectopic event is accompanied by smooth muscle contraction and, although it disrupts the normal propagation pattern of gastric slow electrical waves, it can also catalyse the process of handling indigestible materials that might otherwise injure the gastric SW.
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Affiliation(s)
- Lisa Klemm
- Institute of Mechanics and Adaptronics, Technische Universität Braunschweig, Braunschweig D-38106, Germany
| | - Robert Seydewitz
- Institute of Mechanics and Adaptronics, Technische Universität Braunschweig, Braunschweig D-38106, Germany
| | - Tobias Siebert
- Institute of Sport and Motion Science, University of Stuttgart, Stuttgart D-70569, Germany
| | - Markus Böl
- Institute of Mechanics and Adaptronics, Technische Universität Braunschweig, Braunschweig D-38106, Germany.
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Radu P, Zurzu M, Paic V, Bratucu M, Garofil D, Tigora A, Georgescu V, Prunoiu V, Popa F, Surlin V, Strambu V. Interstitial Cells of Cajal-Origin, Distribution and Relationship with Gastrointestinal Tumors. MEDICINA (KAUNAS, LITHUANIA) 2022; 59:63. [PMID: 36676686 PMCID: PMC9865743 DOI: 10.3390/medicina59010063] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 12/23/2022] [Accepted: 12/25/2022] [Indexed: 12/29/2022]
Abstract
The interstitial cells of Cajal (ICC) represent a particular network formed by some peculiar cells that were first described by the great neuroanatomist, S. Ramon y Cajal. Nowadays, the ICC have become a fascinating topic for scientists, arousing their curiosity; as a result, there is a vast number of published articles related to the ICC. Today, everybody widely accepts that the ICC represent the pacemaker of the gastrointestinal tract and are highly probable to be the origin cells for gastrointestinal tumors (GISTs). Recently, Cajal-like cells (ICLC) were described, which are found in different organs but with an as yet unknown physiological role that needs further study. New information regarding intestinal development indicates that the ICC (fibroblast-like and muscle-like) and intestinal muscle cells have the same common embryonic cells, thereby presenting the same cellular ultrastructure. Nowadays, there is a vast quantity of information that proves the connection of the ICC and GISTs. Both of them are known to present c-kit expression and the same ultrastructural cell features, which includes minimal myoid differentiation that is noticed in GISTs, therefore, supporting the hypothesis that GISTs are ICC-related tumors. In this review, we have tried to highlight the origin and distribution of Cajal interstitial cells based on their ultrastructural features as well as their relationship with gastrointestinal stromal tumors.
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Affiliation(s)
- Petru Radu
- General Surgery Department, Carol Davila Nephrology Hospital Bucharest, 020021 Bucharest, Romania
| | - Mihai Zurzu
- General Surgery Department, Carol Davila Nephrology Hospital Bucharest, 020021 Bucharest, Romania
| | - Vlad Paic
- General Surgery Department, Carol Davila Nephrology Hospital Bucharest, 020021 Bucharest, Romania
| | - Mircea Bratucu
- General Surgery Department, Carol Davila Nephrology Hospital Bucharest, 020021 Bucharest, Romania
| | - Dragos Garofil
- General Surgery Department, Carol Davila Nephrology Hospital Bucharest, 020021 Bucharest, Romania
| | - Anca Tigora
- General Surgery Department, Carol Davila Nephrology Hospital Bucharest, 020021 Bucharest, Romania
| | - Valentin Georgescu
- General Surgery Department, Carol Davila Nephrology Hospital Bucharest, 020021 Bucharest, Romania
| | - Virgiliu Prunoiu
- Oncological Institute “Prof. Dr. Alexandru Trestioreanu”, 022328 Bucharest, Romania
| | - Florian Popa
- General Surgery Department, Carol Davila Nephrology Hospital Bucharest, 020021 Bucharest, Romania
| | - Valeriu Surlin
- Sixth Department of Surgery, University of Medicine and Pharmacy of Craiova, Craiova Emergency Clinical Hospital, 200642 Craiova, Romania
| | - Victor Strambu
- General Surgery Department, Carol Davila Nephrology Hospital Bucharest, 020021 Bucharest, Romania
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Aghababaie Z, O'Grady G, Nisbet LA, Modesto AE, Chan CHA, Matthee A, Amirapu S, Beyder A, Farrugia G, Asirvatham SJ, Sands GB, Paskaranandavadivel N, Cheng LK, Angeli-Gordon TR. Localized bioelectrical conduction block from radiofrequency gastric ablation persists after healing: safety and feasibility in a recovery model. Am J Physiol Gastrointest Liver Physiol 2022; 323:G640-G652. [PMID: 36255716 PMCID: PMC9744642 DOI: 10.1152/ajpgi.00116.2022] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 09/27/2022] [Accepted: 10/13/2022] [Indexed: 01/31/2023]
Abstract
Gastric ablation has demonstrated potential to induce conduction blocks and correct abnormal electrical activity (i.e., ectopic slow-wave propagation) in acute, intraoperative in vivo studies. This study aimed to evaluate the safety and feasibility of gastric ablation to modulate slow-wave conduction after 2 wk of healing. Chronic in vivo experiments were performed in weaner pigs (n = 6). Animals were randomly divided into two groups: sham-ablation (n = 3, control group; no power delivery, room temperature, 5 s/point) and radiofrequency (RF) ablation (n = 3; temperature-control mode, 65°C, 5 s/point). In the initial surgery, high-resolution serosal electrical mapping (16 × 16 electrodes; 6 × 6 cm) was performed to define the baseline slow-wave activation profile. Ablation (sham/RF) was then performed in the mid-corpus, in a line around the circumferential axis of the stomach, followed by acute postablation mapping. All animals recovered from the procedure, with no sign of perforation or other complications. Two weeks later, intraoperative high-resolution mapping was repeated. High-resolution mapping showed that ablation successfully induced sustained conduction blocks in all cases in the RF-ablation group at both the acute and 2 wk time points, whereas all sham-controls had no conduction block. Histological and immunohistochemical evaluation showed that after 2 wk of healing, the lesions were in the inflammation and early proliferation phase, and interstitial cells of Cajal (ICC) were depleted and/or deformed within the ablation lesions. This safety and feasibility study demonstrates that gastric ablation can safely and effectively induce a sustained localized conduction block in the stomach without disrupting the surrounding slow-wave conduction capability.NEW & NOTEWORTHY Ablation has recently emerged as a tool for modulating gastric electrical activation and may hold interventional potential for disorders of gastric function. However, previous studies have been limited to the acute intraoperative setting. This study now presents the safety of gastric ablation after postsurgical recovery and healing. Localized electrical conduction blocks created by ablation remained after 2 wk of healing, and no perforation or other complications were observed over the postsurgical period.
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Affiliation(s)
- Zahra Aghababaie
- Auckland Bioengineering Institute, University of Auckland, Auckland, New Zealand
| | - Gregory O'Grady
- Auckland Bioengineering Institute, University of Auckland, Auckland, New Zealand
- Department of Surgery, University of Auckland, Auckland, New Zealand
| | - Linley A Nisbet
- Auckland Bioengineering Institute, University of Auckland, Auckland, New Zealand
| | - Andre E Modesto
- Department of Surgery, University of Auckland, Auckland, New Zealand
| | | | - Ashton Matthee
- Auckland Bioengineering Institute, University of Auckland, Auckland, New Zealand
| | - Satya Amirapu
- Histology Laboratory, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
| | - Arthur Beyder
- Division of Gastroenterology and Hepatology, and Enteric Neurosciences Program, Mayo Clinic, Rochester, Minnesota
| | - Gianrico Farrugia
- Division of Gastroenterology and Hepatology, and Enteric Neurosciences Program, Mayo Clinic, Rochester, Minnesota
| | | | - Gregory B Sands
- Auckland Bioengineering Institute, University of Auckland, Auckland, New Zealand
| | | | - Leo K Cheng
- Auckland Bioengineering Institute, University of Auckland, Auckland, New Zealand
- Department of Surgery, Vanderbilt University, Nashville, Tennessee
| | - Timothy R Angeli-Gordon
- Auckland Bioengineering Institute, University of Auckland, Auckland, New Zealand
- Department of Surgery, University of Auckland, Auckland, New Zealand
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Ai L, Zhang L, Liang Q, Tian Y, Chen T, Wu C. Investigation of the improving effect of raw and charred hawthorn on functional dyspepsia based on interstitial cells of Cajal. FRONTIERS IN SUSTAINABLE FOOD SYSTEMS 2022. [DOI: 10.3389/fsufs.2022.1010556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
BackgroundRaw hawthorn (RH) is a traditional Chinese medicine commonly used to treat indigestion. Charred hawthorn (CH) is obtained from RH by charring. It is reported that the effect of CH treatment on dyspepsia is stronger than RH. However, this has not been fully proven. The purpose of this study was to compare the effects of RH and CH on functional dyspepsia (FD) model rats. And contribute to the development of dietary therapy for dyspepsia.MethodsSPF-grade male SD rats were divided into 5 groups: the control group, the model group, the Mos group, the RH group, and the CH group. The FD rat model was established by using the methods of water restriction, fasting, tilting cage restraint, day and night upside down, swimming, and tail damping. The body weight of rats in each group was recorded. And the gastric emptying rate, intestinal propulsive rate, and the levels of motilin (MTL), gastrin (GAS), and 5-HT in serum were compared in each group. The expression of C-kit in the stomach and small intestine of each group was compared by immunofluorescence and PCR.ResultsRH and CH could increase weight, improve the gastric emptying rate and intestinal propulsive rate, and promote the secretion of motilin (MTL), gastrin (GAS), and 5-HT in the serum of FD rats. RH and CH can upregulate the expression of the characteristic protein c-kit of ICC in the stomach and small intestine of FD model rats, and the effect of CH is stronger than RH.ConclusionRH and CH may increase the number of interstitial cells of Cajal (ICC) in the gastrointestinal tract by upregulating c-kit expression, thus improving gastrointestinal motility in FD model rats. And compared with RH, CH has certain advantages.
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Jia Q, Li L, Wang X, Wang Y, Jiang K, Yang K, Cong J, Cai G, Ling J. Hesperidin promotes gastric motility in rats with functional dyspepsia by regulating Drp1-mediated ICC mitophagy. Front Pharmacol 2022; 13:945624. [PMID: 36034863 PMCID: PMC9412972 DOI: 10.3389/fphar.2022.945624] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 07/05/2022] [Indexed: 11/22/2022] Open
Abstract
Hesperidin is one of the main active ingredients of Citrus aurantiumL. (Rutaceae) and tangerine peel, which have anti-inflammatory and antioxidant effects. In previous study, we found that gastric motility disorder in functional dyspepsia (FD) rats accompanied by excessive autophagy/mitochondrial swelling and even vacuolization in the interstitial cells of cajal (ICC), but the exact mechanism has not yet been investigated. Therefore, we used different doses of hesperidin (50 mg/kg, 100 mg/kg, and 200 mg/kg) to intervene in FD rats, and found that medium doses of hesperidin (100 mg/kg) significantly increased gastric motility in FD rats. Subsequently, FD rats were randomly divided into control group, model group, mdivi-1 group, mdivi-1+hesperidin group and hesperidin group, and mitochondrial division inhibitor (mdivi-1) was injected intraperitoneally to further investigate whether hesperidin could regulate dynamin-related protein 1 (Drp1)-mediated mitophagy in ICC to improve mitochondrial damage. The results showed that compared with the model group, the serum malondialdehyde (MDA) level decreased and the superoxide dismutase (SOD) level increased in the mdivi-1 and hesperidin groups (p < 0.001). Transmission electron microscopy (TEM) observed that the mitochondrial nuclear membrane was intact in gastric tissues with a clear internal cristae pattern, and autophagy lysosomes were rare. The co-localization expression of microtubule associated protein 1 light chain 3 (LC3) and voltage dependent anion channel 1 (VDAC1), Drp1 and translocase of the outer mitochondrial membrane 20 (Tom20) was significantly decreased (p < 0.001), the protein expression of mitochondrial Drp1, Beclin1 and LC3 were significantly decreased (p < 0.001), the protein expression of mitochondrial P62 and ckit in gastric tissue were significantly increased (p < 0.05, p < 0.001). The above situation was improved more significantly by the synergistic intervention of mdivi-1 and hesperidin. Therefore, hesperidin can improve mitochondrial damage and promote gastric motility in FD rats by regulating Drp1-mediated ICC mitophagy.
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Affiliation(s)
| | | | | | | | | | | | | | - Gan Cai
- *Correspondence: Gan Cai, ; Jianghong Ling,
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Nagahawatte ND, Cheng LK, Avci R, Bear LR, Paskaranandavadivel N. A generalized framework for pacing artifact removal using a Hampel filter. ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. ANNUAL INTERNATIONAL CONFERENCE 2022; 2022:2009-2012. [PMID: 36086179 DOI: 10.1109/embc48229.2022.9871096] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Cardiac pacing is a clinical therapy widely used for treating irregular heart rhythms. Equivalent techniques for the treatment of gastric functional motility disorders hold great potential. Accurate analysis of pacing studies is often hindered by the stimulus artifacts which are superimposed on the recorded signals. This paper presents a semi-automated artifact detection method using a Hampel filter accompanied by 2 separate artifact reconstruction methods: (i) an auto-regressive model, and (ii) weighted mean to estimate the underlying signal. The developed framework was validated on synthetic and experimental signals containing large periodic pacing artifacts alongside evoked bioelectrical events. The performance of the proposed algorithms was quantified for gastric and cardiac pacing data collected in vivo. A lower mean RMS difference was achieved by the artifact segment reconstructed using the auto-regression ([Formula: see text]), method compared to the weighted mean ([Formula: see text]) method. Therefore, a more accurate artifact reconstruction was provided by the auto-regression approach. Clinical Relevance- The ability to efficiently and accurately isolate evoked bioelectrical events by eliminating large artifacts is a critical advancement for the analysis of paced recordings. The developed framework allows more efficient analysis of preclinical pacing data and thereby contributes to the advancement of pacing as a clinical therapy.
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11
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Foong D, Liyanage L, Zhou J, Zarrouk A, Ho V, O'Connor MD. Single-cell RNA sequencing predicts motility networks in purified human gastric interstitial cells of Cajal. Neurogastroenterol Motil 2022; 34:e14303. [PMID: 34913225 DOI: 10.1111/nmo.14303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 10/25/2021] [Accepted: 11/17/2021] [Indexed: 01/19/2023]
Abstract
BACKGROUND Gastrointestinal (GI) motility disorders affect millions of people worldwide, yet they remain poorly treated in part due to insufficient knowledge of the molecular networks controlling GI motility. Interstitial cells of Cajal (ICC) are critical GI pacemaker cells, and abnormalities in ICC are implicated in GI motility disorders. Two cell surface proteins, KIT and ANO1, are used for identifying ICC. However, difficulties accessing human tissue and the low frequency of ICC in GI tissues have meant human ICC are insufficiently characterized. Here, a range of characterization assays including single-cell RNA sequencing (scRNA-seq) was performed using KIT+ CD45- CD11B- primary human gastric ICC to better understand networks controlling human ICC biology. METHODS Excess sleeve gastrectomy tissues were dissected; ICC were analyzed by immunofluorescence, fluorescence-activated cell sorting (FACSorting), real-time PCR, mass spectrometry, and scRNA-seq. KEY RESULTS Immunofluorescence identified ANO1+ /KIT+ cells throughout the gastric muscle. Compared to the FACSorted negative cells, PCR showed the KIT+ CD45- CD11B- ICC were enriched 28-fold in ANO1 expression (p < 0.01). scRNA-seq analysis of the KIT- CD45+ CD11B+ and KIT+ CD45- CD11B- ICC revealed separate clusters of immune cells and ICC (respectively); cells in the ICC cluster expressed critical GI motility genes (eg, CAV1 and PRKG1). The scRNA-seq data for these two cell clusters predicted protein interaction networks consistent with immune cell and ICC biology, respectively. CONCLUSIONS & INFERENCES The single-cell transcriptome of purified KIT+ CD45- CD11B- human gastric ICC presented here provides new molecular insights and hypotheses into evolving models of GI motility. This knowledge will provide an improved framework to investigate targeted therapies for GI motility disorders.
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Affiliation(s)
- Daphne Foong
- School of Medicine, Western Sydney University, Campbelltown, New South Wales, Australia
| | - Liwan Liyanage
- School of Computing, Data and Mathematical Sciences, Western Sydney University, Campbelltown, New South Wales, Australia
| | - Jerry Zhou
- School of Medicine, Western Sydney University, Campbelltown, New South Wales, Australia
| | - Ali Zarrouk
- Campbelltown Private Hospital, Campbelltown, New South Wales, Australia
| | - Vincent Ho
- School of Medicine, Western Sydney University, Campbelltown, New South Wales, Australia.,Campbelltown Private Hospital, Campbelltown, New South Wales, Australia
| | - Michael D O'Connor
- School of Medicine, Western Sydney University, Campbelltown, New South Wales, Australia
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Choi NR, Park J, Ko SJ, Kim JN, Choi W, Park JW, Kim BJ. Prediction of the Medicinal Mechanisms of Pinellia ternata Breitenbach, a Traditional Medicine for Gastrointestinal Motility Disorders, through Network Pharmacology. PLANTS (BASEL, SWITZERLAND) 2022; 11:1348. [PMID: 35631773 PMCID: PMC9145079 DOI: 10.3390/plants11101348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 05/12/2022] [Accepted: 05/16/2022] [Indexed: 12/02/2022]
Abstract
Pinellia ternata Breitenbach (PTB) is a widely used herbal medicine in China, Japan, and South Korea. It has antiemetic, anti-inflammatory, antitussive, and sedative properties. The raw material is toxic, but can be made safer using alum solution or by boiling it for a long time. In addition, PTB seems to be effective for gastrointestinal motility disorders (GMDs), but this is yet to be conclusively proven. Herein, PTB compounds, targets, and related diseases were investigated using the traditional Chinese medical systems pharmacology database and an analysis platform. Information on target genes was confirmed using the UniProt database. Using Cytoscape 3.8.2, a network was established and GMD-related genes were searched using the Cytoscape stringApp. The effects of the PTB extract on the pacemaker potential of interstitial cells of Cajal and GMD mouse models were investigated. In total, 12 compounds were found to target 13 GMD-related genes. In animal experiments, PTB was found to better regulate pacemaker potential in vitro and inhibit GMD signs compared to control groups in vivo. Animal studies showed that the mechanism underlying the effects of PTB is closely related to gastrointestinal motility. The results obtained demonstrated that PTB offers a potential means to treat GMDs, and we suggested that the medicinal mechanism of GMDs can be explained by the relationship between 12 major components of PTB, including oleic acid, and 13 GMD-related genes.
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Affiliation(s)
- Na Ri Choi
- Division of Longevity and Biofunctional Medicine, School of Korean Medicine, Pusan National University, Yangsan 50612, Korea; (N.R.C.); (J.N.K.); (W.C.)
| | - Jongwon Park
- Department of Clinical Korean Medicine, Graduate School of Kyung Hee University, Seoul 02447, Korea; (J.P.); (S.-J.K.)
| | - Seok-Jae Ko
- Department of Clinical Korean Medicine, Graduate School of Kyung Hee University, Seoul 02447, Korea; (J.P.); (S.-J.K.)
- Department of Gastroenterology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea
| | - Jeong Nam Kim
- Division of Longevity and Biofunctional Medicine, School of Korean Medicine, Pusan National University, Yangsan 50612, Korea; (N.R.C.); (J.N.K.); (W.C.)
| | - Woogyun Choi
- Division of Longevity and Biofunctional Medicine, School of Korean Medicine, Pusan National University, Yangsan 50612, Korea; (N.R.C.); (J.N.K.); (W.C.)
| | - Jae-Woo Park
- Department of Clinical Korean Medicine, Graduate School of Kyung Hee University, Seoul 02447, Korea; (J.P.); (S.-J.K.)
- Department of Gastroenterology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea
| | - Byung Joo Kim
- Division of Longevity and Biofunctional Medicine, School of Korean Medicine, Pusan National University, Yangsan 50612, Korea; (N.R.C.); (J.N.K.); (W.C.)
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Effects of sacral nerve stimulation on neuronal nitric oxide synthase in the colon and sacral cord of rats with defecation disorder after spinal cord injury. World Neurosurg 2022; 164:e214-e223. [DOI: 10.1016/j.wneu.2022.04.080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Accepted: 04/19/2022] [Indexed: 11/18/2022]
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Huizinga JD, Hussain A, Chen JH. Interstitial cells of Cajal and human colon motility in health and disease. Am J Physiol Gastrointest Liver Physiol 2021; 321:G552-G575. [PMID: 34612070 DOI: 10.1152/ajpgi.00264.2021] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Our understanding of human colonic motility, and autonomic reflexes that generate motor patterns, has increased markedly through high-resolution manometry. Details of the motor patterns are emerging related to frequency and propagation characteristics that allow linkage to interstitial cells of Cajal (ICC) networks. In studies on colonic motor dysfunction requiring surgery, ICC are almost always abnormal or significantly reduced. However, there are still gaps in our knowledge about the role of ICC in the control of colonic motility and there is little understanding of a mechanistic link between ICC abnormalities and colonic motor dysfunction. This review will outline the various ICC networks in the human colon and their proven and likely associations with the enteric and extrinsic autonomic nervous systems. Based on our extensive knowledge of the role of ICC in the control of gastrointestinal motility of animal models and the human stomach and small intestine, we propose how ICC networks are underlying the motor patterns of the human colon. The role of ICC will be reviewed in the autonomic neural reflexes that evoke essential motor patterns for transit and defecation. Mechanisms underlying ICC injury, maintenance, and repair will be discussed. Hypotheses are formulated as to how ICC dysfunction can lead to motor abnormalities in slow transit constipation, chronic idiopathic pseudo-obstruction, Hirschsprung's disease, fecal incontinence, diverticular disease, and inflammatory conditions. Recent studies on ICC repair after injury hold promise for future therapies.
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Affiliation(s)
- Jan D Huizinga
- Division of Gastroenterology, Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Amer Hussain
- Division of Gastroenterology, Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Ji-Hong Chen
- Division of Gastroenterology, Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
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15
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Nagahawatte ND, Paskaranandavadivel N, Cheng LK. Characterization of Slow Wave Activity in Ex-vivo Porcine Small Intestine Segments. ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. ANNUAL INTERNATIONAL CONFERENCE 2021; 2021:7296-7299. [PMID: 34892783 DOI: 10.1109/embc46164.2021.9630710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
The motility of the gut is central to digestion and is coordinated, in part, by bioelectrical events known as slow waves. While the nature of these events is well defined in-vivo, the temporal response of ex-vivo gastrointestinal myoelectrical activity without perfusion is poorly understood. To achieve a fundamental understanding of ex-vivo electrophysiology, slow wave activity was measured from excised porcine intestinal segments and characterized over time. In this study, slow wave frequencies and amplitudes, along with the duration of sustained activity were quantified. Slow wave amplitudes and frequencies decreased from initial values of 46 ± 34 µV and 9.6 ± 5.9 cpm to electrical quiescence over a period of 12.2 ± 2.3 minutes. Mean slow wave amplitude and frequency uniformly declined before electrical quiescence was reached. This study demonstrated the successful acquisition of gastrointestinal myoelectrical activity in excised tissue segments without perfusion. Key slow wave characteristics may contribute to future diagnostics, transplantations and treatments for motility disorders.Clinical Relevance- The ability to characterize excised slow wave activity in organs lacking perfusion will be a critical advancement in developing clinical solutions. Findings will assist in establishing the efficacy of bioelectrical activity in excised tissue samples for organ transplantation. In addition, the ex-vivo setting can be used to represent compromised electrophysiological states to evaluate novel therapies.
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Del Alcazar CM, Mahoney JA, Dittrich K, Stefanovski D, Church ME. Outcome, prognostic factors and histological characterization of canine gastrointestinal sarcomas. Vet Comp Oncol 2021; 19:578-586. [PMID: 33774909 DOI: 10.1111/vco.12696] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 03/24/2021] [Accepted: 03/24/2021] [Indexed: 12/31/2022]
Abstract
Canine gastrointestinal sarcomas, a group of tumours that includes leiomyosarcomas (LMSAs), gastrointestinal stromal tumours (GISTs) and other rarer sarcomas, comprise about 10-30% of all gastrointestinal tumours. This study aims to characterize the histologic characteristics and clinical behaviour in order to identify prognostic factors predictive of outcome. A single institution database search for surgically treated gastrointestinal sarcomas yielded 47 cases with adequate tissue remaining for histologic analysis and 42 cases available for analysis of clinical outcome. Tumours were then prospectively evaluated for mitotic count, necrosis, haemorrhage and inflammation, as well as categorized via immunohistochemical (IHC) staining for smooth muscle actin, c-KIT and DOG-1. IHC analysis defined 32 tumours as GISTs, 14 as LMSAs and one as a sarcoma not otherwise specified. For both GISTs and LMSAs, the overall median survival time (MST) is 1024 days (range 31-1456), which did not differ statistically between tumour types (p = .92). The overall metastatic rate of GISTs in this study was 32.1% (n = 9) which was not significantly different to that of LMSAs at 15.3% (n = 2, p = .45). In multivariate analysis, mitotic count under 9 in GIST patients and complete surgical excision in all tumour types correlated with improved MST. For patients with GISTs, the intensity of c-KIT staining also correlated positively with survival, with an MST of 250 days in cases with weak staining and an MST of 1418 days in cases with moderate or strong c-KIT staining (p = .005).
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Affiliation(s)
- Chelsea M Del Alcazar
- University of Pennsylvania School of Veterinary Medicine Philadelphia, Philadelphia, Pennsylvania, USA.,Friendship Hospital for Animals, Washington, District of Columbia, USA
| | - Jennifer A Mahoney
- University of Pennsylvania School of Veterinary Medicine Philadelphia, Philadelphia, Pennsylvania, USA
| | - Katherine Dittrich
- University of Pennsylvania School of Veterinary Medicine Philadelphia, Philadelphia, Pennsylvania, USA.,Cummings School of Veterinary Medicine at Tufts University, North Grafton, Massachusetts, USA
| | - Darko Stefanovski
- University of Pennsylvania School of Veterinary Medicine Philadelphia, Philadelphia, Pennsylvania, USA
| | - Molly E Church
- University of Pennsylvania School of Veterinary Medicine Philadelphia, Philadelphia, Pennsylvania, USA
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17
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Kim B, Kwon H, Kim J, Kwon M, Lee J, Kim S, Nam J. The traditional medicine bojungikki-tang increases intestinal motility. Pharmacogn Mag 2021. [DOI: 10.4103/pm.pm_507_20] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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18
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Foong D, Zhou J, Zarrouk A, Ho V, O’Connor MD. Understanding the Biology of Human Interstitial Cells of Cajal in Gastrointestinal Motility. Int J Mol Sci 2020; 21:ijms21124540. [PMID: 32630607 PMCID: PMC7352366 DOI: 10.3390/ijms21124540] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 06/19/2020] [Accepted: 06/23/2020] [Indexed: 12/11/2022] Open
Abstract
Millions of patients worldwide suffer from gastrointestinal (GI) motility disorders such as gastroparesis. These disorders typically include debilitating symptoms, such as chronic nausea and vomiting. As no cures are currently available, clinical care is limited to symptom management, while the underlying causes of impaired GI motility remain unaddressed. The efficient movement of contents through the GI tract is facilitated by peristalsis. These rhythmic slow waves of GI muscle contraction are mediated by several cell types, including smooth muscle cells, enteric neurons, telocytes, and specialised gut pacemaker cells called interstitial cells of Cajal (ICC). As ICC dysfunction or loss has been implicated in several GI motility disorders, ICC represent a potentially valuable therapeutic target. Due to their availability, murine ICC have been extensively studied at the molecular level using both normal and diseased GI tissue. In contrast, relatively little is known about the biology of human ICC or their involvement in GI disease pathogenesis. Here, we demonstrate human gastric tissue as a source of primary human cells with ICC phenotype. Further characterisation of these cells will provide new insights into human GI biology, with the potential for developing novel therapies to address the fundamental causes of GI dysmotility.
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Affiliation(s)
- Daphne Foong
- School of Medicine, Western Sydney University, Campbelltown, NSW 2560, Australia; (D.F.); (J.Z.); (V.H.)
| | - Jerry Zhou
- School of Medicine, Western Sydney University, Campbelltown, NSW 2560, Australia; (D.F.); (J.Z.); (V.H.)
| | - Ali Zarrouk
- Campbelltown Private Hospital, Campbelltown, NSW 2560, Australia;
| | - Vincent Ho
- School of Medicine, Western Sydney University, Campbelltown, NSW 2560, Australia; (D.F.); (J.Z.); (V.H.)
- Campbelltown Private Hospital, Campbelltown, NSW 2560, Australia;
| | - Michael D. O’Connor
- School of Medicine, Western Sydney University, Campbelltown, NSW 2560, Australia; (D.F.); (J.Z.); (V.H.)
- Correspondence:
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20
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Li S, Hu X, Tian R, Guo Y, Chen J, Li Z, Zhao X, Kuang L, Ran D, Zhao H, Zhang X, Wang J, Xia L, Yue J, Yao G, Fu Q, Shi H. RNA-Seq-based transcriptomic profiling of primary interstitial cells of Cajal in response to bovine viral diarrhea virus infection. Vet Res Commun 2019; 43:143-153. [PMID: 31102142 DOI: 10.1007/s11259-019-09754-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2018] [Accepted: 04/30/2019] [Indexed: 12/19/2022]
Abstract
Infections with bovine viral diarrhea virus (BVDV) contribute significantly to health-related economic losses in the beef and dairy industries and are widespread throughout the world. Severe acute BVDV infection is characterized by a gastrointestinal (GI) inflammatory response. The mechanism of inflammatory lesions caused by BVDV remains unknown. The interstitial cells of Cajal (ICC) network plays a pivotal role as a pacemaker in the generation of electrical slow waves for GI motility, and it is crucial for the reception of regulatory inputs from the enteric nervous system. The present study investigated whether ICC were a good model for studying GI inflammatory lesions caused by BVDV infection. Primary ICC were isolated from the duodenum of Merino sheep. The presence of BVDV was detected in ICC grown for five passages after BVDV infection, indicating that BVDV successfully replicated in ICC. After infection with BVDV strain TC, the cell proliferation proceeded slowly or declined. Morphological changes, including swelling, dissolution, and formation of vacuoles in the ICC were observed, indicating quantitative, morphological and functional changes in the cells. RNA sequencing (RNA-Seq) was performed to investigate differentially expressed genes (DEGs) in BVDV-infected ICC and explore the molecular mechanism of underlying quantitative, morphological and functional changes of ICC. Eight hundred six genes were differentially expressed after BVDV infection, of which 538 genes were upregulated and 268 genes were downregulated. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses showed that the 806 DEGs were significantly enriched in 27 pathways, including cytokine-cytokine receptor interaction, interleukin (IL)-17 signaling and mitogen-activated protein kinase (MAPK) signaling pathways. The DEGs and raw files of high-throughput sequencing of this study were submitted to the NCBI Gene Expression Omnibus (GEO) database (accession number GSE122344). Finally, 21 DEGs were randomly selected, and the relative repression levels of these genes were tested using the quantitative real-time PCR (qRT-PCR) to validate the RNA-Seq results. The results showed that the related expression levels of 21 DEGs were similar to RNA-Seq. This study is the first to establish a new infection model for investigating GI inflammatory lesions induced by BVDV infection. RNA-Seq-based transcriptomic profiling can provide a basis for study on BVDV-associated inflammatory lesions.
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Affiliation(s)
- Shengnan Li
- College of Veterinary Medicine, Xinjiang Agricultural University, Urumqi, 830052, Xinjiang, China
| | - Xinyan Hu
- College of Veterinary Medicine, Xinjiang Agricultural University, Urumqi, 830052, Xinjiang, China
| | - Ruixin Tian
- College of Veterinary Medicine, Xinjiang Agricultural University, Urumqi, 830052, Xinjiang, China
| | - Yanting Guo
- College of Veterinary Medicine, Xinjiang Agricultural University, Urumqi, 830052, Xinjiang, China
| | - Junzhen Chen
- College of Veterinary Medicine, Xinjiang Agricultural University, Urumqi, 830052, Xinjiang, China
| | - Zhen Li
- College of Veterinary Medicine, Xinjiang Agricultural University, Urumqi, 830052, Xinjiang, China
| | - Xinyan Zhao
- College of Veterinary Medicine, Xinjiang Agricultural University, Urumqi, 830052, Xinjiang, China
| | - Ling Kuang
- College of Veterinary Medicine, Xinjiang Agricultural University, Urumqi, 830052, Xinjiang, China
| | - Duoliang Ran
- College of Veterinary Medicine, Xinjiang Agricultural University, Urumqi, 830052, Xinjiang, China
| | - Hongqiong Zhao
- College of Veterinary Medicine, Xinjiang Agricultural University, Urumqi, 830052, Xinjiang, China
| | - Xiaohong Zhang
- College of Veterinary Medicine, Xinjiang Agricultural University, Urumqi, 830052, Xinjiang, China
| | - Jinquan Wang
- College of Veterinary Medicine, Xinjiang Agricultural University, Urumqi, 830052, Xinjiang, China
| | - Lining Xia
- College of Veterinary Medicine, Xinjiang Agricultural University, Urumqi, 830052, Xinjiang, China
| | - Jianbo Yue
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China
| | - Gang Yao
- College of Veterinary Medicine, Xinjiang Agricultural University, Urumqi, 830052, Xinjiang, China.
| | - Qiang Fu
- College of Veterinary Medicine, Xinjiang Agricultural University, Urumqi, 830052, Xinjiang, China.
| | - Huijun Shi
- College of Veterinary Medicine, Xinjiang Agricultural University, Urumqi, 830052, Xinjiang, China.
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Radhika Krishna OH, Aleem MA, Kayla G. Abnormalities of the intestinal pacemaker cells, enteric neurons, and smooth muscle in intestinal atresia. J Lab Physicians 2019; 11:180-185. [PMID: 31579250 PMCID: PMC6771318 DOI: 10.4103/jlp.jlp_94_18] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2018] [Accepted: 02/09/2019] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Small bowel atresia is a congenital disorder that carves a substantial morbidity. Numerous postoperative gastrointestinal motility problems occur. The underlying cause of this motility disorder is still unclear. Interstitial cells of Cajal (ICC) play a major role in gastrointestinal motility. AIMS AND OBJECTIVES To investigate the morphological changes of enteric nervous system and ICC in small bowel atresia. MATERIAL AND METHODS Resected small bowel specimen from affected patients (n=15) were divided into three parts (proximal, distal, atretic). Standard histology and immunohistochemistry with anti C-KIT receptor antibody (CD117), calretinin and α-SMA was carried out. The density of myenteric ICCs in the proximal, atretic and distal parts was demonstrated by CD 117 while Calretinin was used for ganglion cells and nerve bundles, α-SMA highlighted muscle hypertrophy. RESULT AND CONCLUSION The proximal and distal bowel revealed clear changes in the morphology and density of enteric nervous system and interstitial cells of Cajal..
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Affiliation(s)
- OH Radhika Krishna
- Department of Pathology, Niloufer Hospital for Women and Children, Hyderabad, Telangana, India
| | - Mohammed Abdul Aleem
- Department of Pathology, Niloufer Hospital for Women and Children, Hyderabad, Telangana, India
| | - Geetha Kayla
- Department of Pathology, Niloufer Hospital for Women and Children, Hyderabad, Telangana, India
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DeSimone CV, McLeod CJ, Gomez Pinilla PJ, Beyder A, Farrugia G, Asirvatham SJ, Kapa S. Telocytes express ANO-1-encoded chloride channels in canine ventricular myocardium. J Arrhythm 2019; 35:515-521. [PMID: 31293701 PMCID: PMC6595329 DOI: 10.1002/joa3.12176] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2018] [Revised: 01/30/2019] [Accepted: 02/22/2019] [Indexed: 12/17/2022] Open
Abstract
INTRODUCTION It is unknown if ANO-1 is expressed in the heart, though the presence of a calcium-activated chloride current has been proposed to mediate some cardiac dysrhythmias. Furthermore, a specific cell type termed telocytes, morphologically mimicking Cajal cells which use ANO-1 to modulate their pacemaker activity in the gut, have been described in the heart. We therefore sought to determine whether this channel is expressed in the canine heart. METHODS Myocardium was sampled from the ventricles of five canines. Sections were labeled with anti-Kit and anti-ANO-1 antibodies. Slides were reviewed by four investigators looking at cell morphology, distribution, and co-localization. Identification of telocytes was based on criteria including morphology, Kit positivity (+), and ANO-1 positivity (+). RESULTS Clusters of cells meeting criteria for telocytes were seen in the epicardium, sub-epicardium, and mid-myocardium. A small subset of cells that were morphologically similar to myocytes was ANO-1 (+) but Kit (-). In total, three different cell classes were found: (i) Kit (+), ANO-1 (+) cells with the appearance of telocytes; (ii) Kit (+), ANO-1 (-) cells; and (iii) Kit (-), ANO-1 (+) cells with the morphologic appearance of cardiac myocytes. CONCLUSIONS Telocytes are present in the canine ventricle and express ANO-1. These data merit further study to elucidate the functional expression of these channels in the heart and whether they may be targets for cardiac arrhythmias.
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Affiliation(s)
| | | | | | - Arthur Beyder
- Division of GastroenterologyDepartment of Internal MedicineMayo ClinicRochesterMNUSA
| | - Gianrico Farrugia
- Division of GastroenterologyDepartment of Internal MedicineMayo ClinicRochesterMNUSA
| | - Samuel J. Asirvatham
- Division of CardiologyDepartment of Internal MedicineMayo ClinicRochesterMNUSA
- Division of Pediatric CardiologyDepartment of Pediatrics and Adolescent MedicineMayo ClinicRochesterMNUSA
| | - Suraj Kapa
- Division of CardiologyDepartment of Internal MedicineMayo ClinicRochesterMNUSA
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den Braber-Ymker M, Heijker S, Lammens M, Croockewit S, Nagtegaal ID. Intestinal involvement in amyloidosis is a sequential process. Neurogastroenterol Motil 2018; 30:e13469. [PMID: 30230124 DOI: 10.1111/nmo.13469] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Revised: 08/10/2018] [Accepted: 08/14/2018] [Indexed: 12/22/2022]
Abstract
BACKGROUND Gastrointestinal amyloidosis causes dysmotility. A comprehensive histological analysis to explain these symptoms is lacking. Therefore, we systematically examined histological features of intestinal dysmotility in patients with AL and AA amyloidosis, compared to controls. METHODS Autopsy tissue material from small bowel and colon was used for histological (semiquantitative) evaluation of the mucosa, blood vessels, muscular layers, enteric nervous system (ENS) and the interstitial cells of Cajal (ICC), using hematoxylin and eosin, periodic acid Schiff, Elastic von Gieson and Congo red staining, and immunohistochemistry with α-smooth muscle actin, HuC/D, S100 and CD117 antibodies, according to guidelines of the Gastro 2009 International Working Group. KEY RESULTS Amyloid deposits were present in the vascular walls of all amyloidosis patients. In the mucosa, amyloid was found in 67% of AA patients. The muscular layers were involved in 64% of amyloidosis patients, most prominent in AA patients, associated with the presence of polyglucosan inclusion bodies, but not with either abnormal α-actin patterns or fibrosis. Amyloid in the muscularis propria surrounding the myenteric plexus was found, but not inside the myenteric plexus. These deposits might be related to loss of the ICC network, but there was no association with decreased neuronal or nerve fiber density. CONCLUSIONS & INFERENCES We hypothesize that intestinal dysmotility in amyloidosis patients is a sequential process: amyloid deposition starts in the vasculature, followed by involvement of the muscular layers, ICC loss, and potentially affect the myenteric plexus. This final stage may be accompanied by clinical symptoms of severe intestinal dysmotility.
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Affiliation(s)
| | - Sanneke Heijker
- Department of Pathology, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, The Netherlands
| | - Martin Lammens
- Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands.,Department of Pathology, Antwerp University Hospital, University of Antwerp, Edegem, Belgium.,MIPRO, University of Antwerp, Antwerp, Belgium
| | - Sandra Croockewit
- Department of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Iris D Nagtegaal
- Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands
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Bure I, Geer S, Knopf J, Roas M, Henze S, Ströbel P, Agaimy A, Wiemann S, Hoheisel JD, Hartmann A, Haller F, Moskalev EA. Long noncoding RNA HOTAIR is upregulated in an aggressive subgroup of gastrointestinal stromal tumors (GIST) and mediates the establishment of gene-specific DNA methylation patterns. Genes Chromosomes Cancer 2018; 57:584-597. [PMID: 30248209 DOI: 10.1002/gcc.22672] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Revised: 07/23/2018] [Accepted: 07/24/2018] [Indexed: 01/17/2023] Open
Abstract
Aberrant alterations of DNA methylation are common events in oncogenesis. The origin of cancer-associated epigenetic defects is of interest for mechanistic understanding of malignant transformation and-in the long run-therapeutic modulation of DNA methylation in a locus-specific manner. Given the ability of certain long noncoding RNAs to operate as an interface between DNA and the epigenetic modification machinery which can interact with DNA methyltransferases, we hypothesized-considering HOTAIR as an example-that this transcript may contribute to gene specificity of DNA methylation. Using gastrointestinal stromal tumors (GISTs, n = 67) as a model, we confirmed upregulation of HOTAIR in tumors with high risk of recurrence and showed high abundance of the transcript in GIST cell lines. HOTAIR knockdown in GIST-T1 cells triggered transcriptional response of genes involved in the organization and disassembly of the extracellular matrix and, notably, induced global locus-specific alterations of DNA methylation patterns. Hypomethylation was induced at a total of 507 CpG sites, whereas 382 CpG dinucleotides underwent gain of methylation upon HOTAIR depletion. Importantly, orchestrated gain or loss of methylation at multiple individual CpG sites was shown for cancer-related DPP4, RASSF1, ALDH1A3, and other targets. Collectively, our data indicate that HOTAIR enables target specificity of DNA methylation in GIST and is capable of dual (hypo- and hypermethylation) regulation by a yet to be defined mechanism. The results further suggest the feasibility of manipulating DNA methylation in a targeted manner and are of interest in the context of epigenetic cancer therapy.
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Affiliation(s)
- Irina Bure
- Diagnostic Molecular Pathology, Institute of Pathology, Friedrich Alexander University, Erlangen, Germany
| | - Sandra Geer
- Diagnostic Molecular Pathology, Institute of Pathology, Friedrich Alexander University, Erlangen, Germany
| | - Jasmin Knopf
- Diagnostic Molecular Pathology, Institute of Pathology, Friedrich Alexander University, Erlangen, Germany
| | - Maike Roas
- Diagnostic Molecular Pathology, Institute of Pathology, Friedrich Alexander University, Erlangen, Germany
| | - Sabine Henze
- Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Philipp Ströbel
- Institute of Pathology, Georg August University, Göttingen, Germany
| | - Abbas Agaimy
- Diagnostic Molecular Pathology, Institute of Pathology, Friedrich Alexander University, Erlangen, Germany
| | - Stefan Wiemann
- Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Molecular Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Jörg D Hoheisel
- Functional Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Arndt Hartmann
- Diagnostic Molecular Pathology, Institute of Pathology, Friedrich Alexander University, Erlangen, Germany
| | - Florian Haller
- Diagnostic Molecular Pathology, Institute of Pathology, Friedrich Alexander University, Erlangen, Germany
| | - Evgeny A Moskalev
- Diagnostic Molecular Pathology, Institute of Pathology, Friedrich Alexander University, Erlangen, Germany
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25
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Ricci R, Giustiniani MC, Gessi M, Lanza P, Castri F, Biondi A, Persiani R, Vecchio FM, Risio M. Telocytes are the physiological counterpart of inflammatory fibroid polyps and PDGFRA-mutant GISTs. J Cell Mol Med 2018; 22:4856-4862. [PMID: 30117724 PMCID: PMC6156396 DOI: 10.1111/jcmm.13748] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2018] [Accepted: 05/29/2018] [Indexed: 12/23/2022] Open
Abstract
PDGFRA mutations in the gastrointestinal (GI) tract can cause GI stromal tumour (GIST) and inflammatory fibroid polyp (IFP). Hitherto no cell type has been identified as a physiological counterpart of the latter, while interstitial Cajal cells (ICC) are considered the precursor of the former. However, ICC hyperplasia (ICCH), which strongly supports the ICC role in GIST pathogenesis, has been identified in germline KIT-mutant settings but not in PDGFRA-mutant ones, challenging the precursor role of ICC for PDGFRA-driven GISTs. Telocytes are a recently described interstitial cell type, CD34+/PDGFRA+. Formerly considered fibroblasts, they are found in many organs, including the GI tract where they are thought to be involved in neurotransmission. Alongside IFPs and gastric GISTs, GI wall "fibrosis" has been reported in germline PDGFRA-mutants. Taking the opportunity offered by its presence in a germline PDGFRA-mutant individual, we demonstrate that this lesion is sustained by hyperplastic telocytes, constituting the PDGFRA-mutant counterpart of germline KIT mutation-associated ICCH. Moreover, our findings support a pathogenetic relationship between telocyte hyperplasia and both IFPs and PDGFRA-mutant GISTs. We propose the term "telocytoma" for defining IFP, as it conveys both the pathogenetic (neoplastic) and histotypic ("telocytary") essence of this tumour, unlike IFP, which rather evokes an inflammatory-hyperplastic lesion.
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Affiliation(s)
- Riccardo Ricci
- Department of Pathology, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario "A. Gemelli", Rome, Italy
| | - Maria Cristina Giustiniani
- Department of Pathology, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario "A. Gemelli", Rome, Italy
| | - Marco Gessi
- Department of Pathology, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario "A. Gemelli", Rome, Italy
| | - Paola Lanza
- Department of Pathology, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario "A. Gemelli", Rome, Italy
| | - Federica Castri
- Department of Pathology, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario "A. Gemelli", Rome, Italy
| | - Alberto Biondi
- Department of Surgery, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario "A. Gemelli", Rome, Italy
| | - Roberto Persiani
- Department of Surgery, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario "A. Gemelli", Rome, Italy
| | - Fabio M Vecchio
- Department of Pathology, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario "A. Gemelli", Rome, Italy
| | - Mauro Risio
- Department of Pathology, Emeritus, IRCC, Candiolo, Italy
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26
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Sun X, Fu X, Du M, Zhu MJ. Ex vivo gut culture for studying differentiation and migration of small intestinal epithelial cells. Open Biol 2018; 8:170256. [PMID: 29643147 PMCID: PMC5936714 DOI: 10.1098/rsob.170256] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2017] [Accepted: 03/09/2018] [Indexed: 12/16/2022] Open
Abstract
Epithelial cultures are commonly used for studying gut health. However, due to the absence of mesenchymal cells and gut structure, epithelial culture systems including recently developed three-dimensional organoid culture cannot accurately represent in vivo gut development, which requires intense cross-regulation of the epithelial layer with the underlying mesenchymal tissue. In addition, organoid culture is costly. To overcome this, a new culture system was developed using mouse embryonic small intestine. Cultured intestine showed spontaneous peristalsis, indicating the maintenance of the normal gut physiological structure. During 10 days of ex vivo culture, epithelial cells moved along the gut surface and differentiated into different epithelial cell types, including enterocytes, Paneth cells, goblet cells and enteroendocrine cells. We further used the established ex vivo system to examine the role of AMP-activated protein kinase (AMPK) on gut epithelial health. Tamoxifen-induced AMPKα1 knockout vastly impaired epithelial migration and differentiation of the developing ex vivo gut, showing the crucial regulatory function of AMPK α1 in intestinal health.
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Affiliation(s)
- Xiaofei Sun
- School of Food Science, Washington State University, Pullman, WA 99164, USA
- School of Food Science, University of Idaho, Moscow, ID 83844, USA
| | - Xing Fu
- Department of Animal Science, Washington State University, Pullman, WA 99164, USA
| | - Min Du
- Department of Animal Science, Washington State University, Pullman, WA 99164, USA
| | - Mei-Jun Zhu
- School of Food Science, Washington State University, Pullman, WA 99164, USA
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27
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Joddar B, Tasnim N, Thakur V, Kumar A, McCallum RW, Chattopadhyay M. Delivery of Mesenchymal Stem Cells from Gelatin-Alginate Hydrogels to Stomach Lumen for Treatment of Gastroparesis. Bioengineering (Basel) 2018; 5:12. [PMID: 29414870 PMCID: PMC5874878 DOI: 10.3390/bioengineering5010012] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2018] [Revised: 02/02/2018] [Accepted: 02/04/2018] [Indexed: 12/12/2022] Open
Abstract
Gastroparesis (GP) is associated with depletion of interstitial cells of Cajal (ICCs) and enteric neurons, which leads to pyloric dysfunction followed by severe nausea, vomiting and delayed gastric emptying. Regenerating these fundamental structures with mesenchymal stem cell (MSC) therapy would be helpful to restore gastric function in GP. MSCs have been successfully used in animal models of other gastrointestinal (GI) diseases, including colitis. However, no study has been performed with these cells on GP animals. In this study, we explored whether mouse MSCs can be delivered from a hydrogel scaffold to the luminal surfaces of mice stomach explants. Mouse MSCs were seeded atop alginate-gelatin, coated with poly-l-lysine. These cell-gel constructs were placed atop stomach explants facing the luminal side. MSCs grew uniformly all across the gel surface within 48 h. When placed atop the lumen of the stomach, MSCs migrated from the gels to the tissues, as confirmed by positive staining with vimentin and N-cadherin. Thus, the feasibility of transplanting a cell-gel construct to deliver stem cells in the stomach wall was successfully shown in a mice stomach explant model, thereby making a significant advance towards envisioning the transplantation of an entire tissue-engineered 'gastric patch' or 'microgels' with cells and growth factors.
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Affiliation(s)
- Binata Joddar
- Inspired Materials & Stem-Cell Based Tissue Engineering Laboratory (IMSTEL), Department of Metallurgical, Materials and Biomedical Engineering, University of Texas at El Paso, 500 W University Avenue, El Paso, TX 79968, USA.
- Border Biomedical Research Center, University of Texas at El Paso, 500 W University Avenue, El Paso, TX 79968, USA.
| | - Nishat Tasnim
- Inspired Materials & Stem-Cell Based Tissue Engineering Laboratory (IMSTEL), Department of Metallurgical, Materials and Biomedical Engineering, University of Texas at El Paso, 500 W University Avenue, El Paso, TX 79968, USA.
| | - Vikram Thakur
- Department of Biomedical Sciences, Center of Emphasis in Diabetes and Metabolism, Texas Tech University Health Sciences Center, 5001 El Paso Drive, El Paso, TX 79905, USA.
| | - Alok Kumar
- Inspired Materials & Stem-Cell Based Tissue Engineering Laboratory (IMSTEL), Department of Metallurgical, Materials and Biomedical Engineering, University of Texas at El Paso, 500 W University Avenue, El Paso, TX 79968, USA.
| | - Richard W McCallum
- Department of Internal Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, 4800 Alberta Avenue, El Paso, TX 79905, USA.
| | - Munmun Chattopadhyay
- Department of Biomedical Sciences, Center of Emphasis in Diabetes and Metabolism, Texas Tech University Health Sciences Center, 5001 El Paso Drive, El Paso, TX 79905, USA.
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28
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Veličkov A, Radenković G, Petrović V, Veličkov A. DIABETIC ALTERATIONS OF INTERSTITIAL CELLS OF CAJAL. ACTA MEDICA MEDIANAE 2017. [DOI: 10.5633/amm.2017.0416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
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Abstract
OPINION STATEMENT Diabetes mellitus (DM) and its associated complications are becoming increasingly prevalent. Gastrointestinal symptoms associated with diabetes is known as diabetic enteropathy (DE) and may manifest as either diarrhea, fecal incontinence, constipation, dyspepsia, nausea, and vomiting or a combination of symptoms. The long-held belief that vagal autonomic neuropathy is the primary cause of DE has recently been challenged by newer theories of disease development. Specifically, hyperglycemia and the resulting oxidative stress on neural networks, including the nitrergic neurons and interstitial cells of Cajal (ICC), are now believed to play a central role in the development of DE. DE occurs in the majority of patients with diabetes; however, tools for early diagnosis and targeted therapy to counter the detrimental and potentially irreversible effects on the small bowel are lacking. Delay in diagnosis is further compounded by the fact that DE symptoms overlap with those of gastroparesis or can be confused with side effects from diabetes medications. Still, early recognition of the presence of DE is essential to mitigating symptoms and preventing further progression of complications including dysmotility and malabsorption. Current diagnostic modalities include manometry, wireless motility capsule (SmartPill™), and scintigraphy; however, these are not regularly utilized in clinical practice due to limited availability. Several medications are available for symptom relief in DE patients including rifaximin for small intestinal bacterial overgrowth (SIBO) and somatostatin analogues for diarrhea. While rodent models on stem cell therapy and alteration of the microbiome are promising, there is still a great need for further research on the pathologic underpinnings and development of novel treatment modalities for DE.
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Affiliation(s)
- Jonathan Gotfried
- Temple University Digestive Disease Center, Temple University Hospital, Philadelphia, PA, USA
| | - Stephen Priest
- Temple University Lewis Katz School of Medicine at Temple University & Temple University Health System, Philadelphia, PA, USA
| | - Ron Schey
- Temple University Digestive Disease Center, Temple University Hospital, Philadelphia, PA, USA. .,Temple University Lewis Katz School of Medicine at Temple University & Temple University Health System, Philadelphia, PA, USA.
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30
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Sanches BDA, Maldarine JS, Zani BC, Tamarindo GH, Biancardi MF, Santos FCA, Rahal P, Góes RM, Felisbino SL, Vilamaior PSL, Taboga SR. Telocytes play a key role in prostate tissue organisation during the gland morphogenesis. J Cell Mol Med 2017; 21:3309-3321. [PMID: 28840644 PMCID: PMC5706570 DOI: 10.1111/jcmm.13234] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Accepted: 04/15/2017] [Indexed: 01/19/2023] Open
Abstract
Telocytes are CD34-positive interstitial cells, known to exert several functions, one of which is a role in tissue organisation, previously demonstrated by telocytes in the myocardium. The existence of telocytes in the prostate has recently been reported, however, there is a lack of information regarding the function of these cells in prostate tissue, and information regarding the possible role of these cells in prostatic development. This study used immunofluorescence techniques in prostate tissue and prostatic telocytes in culture to determine the relationship between telocytes and prostate morphogenesis. Furthermore, immunofluorescent labelling of telocytes was performed on prostate tissue at different stages of early postnatal development. Initially, CD34-positive cells are found at the periphery of the developing alveoli, later in the same region, c-kit-positive cells and cells positive for both factors are verified and CD34-positive cells were predominantly observed in the interalveolar stroma and the region surrounding the periductal smooth muscle. Fluorescence assays also demonstrated that telocytes secrete TGF-β1 and are ER-Beta (ERβ) positive. The results suggest that telocytes play a changing role during development, initially supporting the differentiation of periductal and perialveolar smooth muscle, and later, producing dense networks that separate alveoli groups and form a barrier between the interalveolar region and periurethral smooth muscle. We conclude that telocytes play a relevant role in prostate tissue organisation during postnatal development.
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Affiliation(s)
- Bruno D A Sanches
- Department of Structural and Functional Biology, State University of Campinas, Campinas, São Paulo, Brazil
| | - Juliana S Maldarine
- Department of Biology, Univ. Estadual Paulista (UNESP), São José do Rio Preto, São Paulo, Brazil
| | - Bruno C Zani
- Department of Biology, Univ. Estadual Paulista (UNESP), São José do Rio Preto, São Paulo, Brazil
| | - Guilherme H Tamarindo
- Department of Structural and Functional Biology, State University of Campinas, Campinas, São Paulo, Brazil
| | - Manoel F Biancardi
- Department of Histology, Embryology and Cell Biology, Federal University of Goiás, Goiânia, Goiás, Brazil
| | - Fernanda C A Santos
- Department of Histology, Embryology and Cell Biology, Federal University of Goiás, Goiânia, Goiás, Brazil
| | - Paula Rahal
- Department of Biology, Univ. Estadual Paulista (UNESP), São José do Rio Preto, São Paulo, Brazil
| | - Rejane M Góes
- Department of Biology, Univ. Estadual Paulista (UNESP), São José do Rio Preto, São Paulo, Brazil
| | - Sérgio L Felisbino
- Department of Morphology, Institute of Biology (IB), Univ. Estadual Paulista - UNESP, Botucatu, São Paulo, Brazil
| | - Patricia S L Vilamaior
- Department of Biology, Univ. Estadual Paulista (UNESP), São José do Rio Preto, São Paulo, Brazil
| | - Sebastião R Taboga
- Department of Biology, Univ. Estadual Paulista (UNESP), São José do Rio Preto, São Paulo, Brazil
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31
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Słupecka M, Grzesiak P, Kwiatkowski J, Gajewska M, Kuwahara A, Kato I, Woliński J. The influence of enteral obestatin administration to suckling rats on intestinal contractility. Gen Comp Endocrinol 2017; 248:69-78. [PMID: 28212895 DOI: 10.1016/j.ygcen.2017.02.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2016] [Revised: 01/24/2017] [Accepted: 02/13/2017] [Indexed: 12/13/2022]
Abstract
This study investigated the effect of enteral administration of obestatin on the contractility of whole-thickness preparations of duodenum and middle jejunum, as well as on the morphology of the enteric nervous system (ENS). Suckling rats were assigned to 3 groups (n=12) treated with: C-saline solution; LO-obestatin (125nmol/kgb.wt); HO-obestatin (250nmol/kgb.wt). Saline solution or obestatin were administered twice daily, from the 14th to the 21st day of life. Sections were studied in an organ bath, for isometric recording in the presence of acetylocholine (ACh), atropine (ATR) and tetradotoxin (TTX). Thickness of intestinal muscularis layer, the number of interstitial cells of Cajal (ICC) were measured in the paraffin sections. The immunodetection of Muscarinic Acetylocholine Receptor 2 (M2 receptor) was performed in the intestinal segments. In both intestinal segments HO treatment decreased the amplitude of spontaneous contraction compared to that observed in the C group. In the middle jejunum, the LO treatment also decreased the amplitude. TTX and ATR had no effect on amplitude of spontaneous contraction in the jejunum of LO and HO-treated animals. Compared to the C group, duodenal sections from HO animals and middle jejunum sections from LO and HO groups displayed a lower amplitude in response to ACh and EFS evoked contraction. An increase in the thickness of the muscularis layer was observed in the duodenum of LO and HO groups whereas the number ICC did not change significantly after treatment with obestatin. Moreover, the enteral administration of obestatin did not effect significantly on the cytoplasmic expression of M2 receptor in the jejunum. Our study demonstrated that enteral administration of obestatin to suckling rats influences small intestine contractility in the segment specific manner.
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Affiliation(s)
- M Słupecka
- Department of Animal Physiology, The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, Jabłonna, Poland.
| | - P Grzesiak
- Department of Animal Physiology, The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, Jabłonna, Poland
| | - J Kwiatkowski
- Department of Animal Physiology, The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, Jabłonna, Poland
| | - M Gajewska
- Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences, Warsaw, Poland
| | - A Kuwahara
- Laboratory of Physiology, Institute for Environmental Sciences and Graduate School of Nutritional and Enviromental Science, University of Shizuoka, Japan
| | - I Kato
- Department of Medical Biochemistry, Kobe Pharmaceutical University, Japan
| | - J Woliński
- Department of Animal Physiology, The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, Jabłonna, Poland
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32
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Kiriukhin SO, Makarova OV. [Morphological changes in the colonic muscular layer and interstitial cells of Cajal in experimental acute ulcerative colitis]. Arkh Patol 2017; 78:27-32. [PMID: 27804943 DOI: 10.17116/patol201678527-32] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
AIM to investigate morphological changes in the muscular layer and an intermuscular population of interstitial cells of Cajal (ICC) in acute ulcerative colitis induced by dextran sulfate sodium (DSS). MATERIAL AND METHODS Acute colitis was induced by 3% DSS (molecular weight 40 kDa) in drinking water for 5 days; a control animal group was given tap water. Longitudinal colonic sections were histologically examined. Immunofluorescence staining of total preparations with antibodies to c-Kit was employed to assess an ICC population. RESULTS Morphological examination showed a morphological pattern of acute ulcerative colitis in the DSS-treated mice. The colonic muscular layer was thickened and the cytoplasm of smooth muscle cells was vacuolated. There was a decrease in ICC network density and counts in the muscular layer, as well as a specific c-Kit positive granularity in the ICC bodies and processes. CONCLUSION In acute ulcerative colitis, there are alternative changes in the colonic muscular layer and a decrease in ICC density.
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Affiliation(s)
- S O Kiriukhin
- Research Institute of Human Morphology, Federal Agency for Scientific Organizations of the Russian Federation, Moscow, Russian Federation; M.V. Lomonosov Moscow State University, Moscow, Russia
| | - O V Makarova
- Research Institute of Human Morphology, Federal Agency for Scientific Organizations of the Russian Federation, Moscow, Russian Federation; M.V. Lomonosov Moscow State University, Moscow, Russia
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Zhao M, Liao D, Zhao J. Diabetes-induced mechanophysiological changes in the small intestine and colon. World J Diabetes 2017; 8:249-269. [PMID: 28694926 PMCID: PMC5483424 DOI: 10.4239/wjd.v8.i6.249] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2017] [Revised: 04/05/2017] [Accepted: 05/05/2017] [Indexed: 02/05/2023] Open
Abstract
The disorders of gastrointestinal (GI) tract including intestine and colon are common in the patients with diabetes mellitus (DM). DM induced intestinal and colonic structural and biomechanical remodeling in animals and humans. The remodeling is closely related to motor-sensory abnormalities of the intestine and colon which are associated with the symptoms frequently encountered in patients with DM such as diarrhea and constipation. In this review, firstly we review DM-induced histomorphological and biomechanical remodeling of intestine and colon. Secondly we review motor-sensory dysfunction and how they relate to intestinal and colonic abnormalities. Finally the clinical consequences of DM-induced changes in the intestine and colon including diarrhea, constipation, gut microbiota change and colon cancer are discussed. The final goal is to increase the understanding of DM-induced changes in the gut and the subsequent clinical consequences in order to provide the clinicians with a better understanding of the GI disorders in diabetic patients and facilitates treatments tailored to these patients.
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Wong KKL, Tang LCY, Zhou J, Ho V. Analysis of spatiotemporal pattern and quantification of gastrointestinal slow waves caused by anticholinergic drugs. Organogenesis 2017; 13:39-62. [PMID: 28277890 DOI: 10.1080/15476278.2017.1295904] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
Anticholinergic drugs are well-known to cause adverse effects, such as constipation, but their effects on baseline contractile activity in the gut driven by slow waves is not well established. In a video-based gastrointestinal motility monitoring (GIMM) system, a mouse's small intestine was placed in Krebs solution and recorded using a high definition camera. Untreated controls were recorded for each specimen, then treated with a therapeutic concentration of the drug, and finally, treated with a supratherapeutic dose of the drug. Next, the video clips showing gastrointestinal motility were processed, giving us the segmentation motions of the intestine, which were then converted via Fast Fourier Transform (FFT) into their respective frequency spectrums. These contraction quantifications were analyzed from the video recordings under standardised conditions to evaluate the effect of drugs. Six experimental trials were included with benztropine and promethazine treatments. Only the supratherapeutic dose of benztropine was shown to significantly decrease the amplitude of contractions; at therapeutic doses of both drugs, neither frequency nor amplitude was significantly affected. We have demonstrated that intestinal slow waves can be analyzed based on the colonic frequency or amplitude at a supratherapeutic dose of the anticholinergic medications. More research is required on the effects of anticholinergic drugs on these slow waves to ascertain the true role of ICC in neurologic control of gastrointestinal motility.
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Affiliation(s)
- Kelvin K L Wong
- a School of Medicine, Western Sydney University , Campbelltown , NSW , Australia
| | - Lauren C Y Tang
- a School of Medicine, Western Sydney University , Campbelltown , NSW , Australia
| | - Jerry Zhou
- a School of Medicine, Western Sydney University , Campbelltown , NSW , Australia
| | - Vincent Ho
- a School of Medicine, Western Sydney University , Campbelltown , NSW , Australia
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35
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den Braber-Ymker M, Lammens M, van Putten MJAM, Nagtegaal ID. The enteric nervous system and the musculature of the colon are altered in patients with spina bifida and spinal cord injury. Virchows Arch 2017; 470:175-184. [PMID: 28062917 PMCID: PMC5306076 DOI: 10.1007/s00428-016-2060-4] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Revised: 10/12/2016] [Accepted: 12/20/2016] [Indexed: 12/29/2022]
Abstract
Neurogenic bowel dysfunction occurs in a large percentage of adult patients with spina bifida (SB) and spinal cord injury (SCI), significantly affecting their quality of life. Although bowel motility is autonomously regulated by the enteric nervous system (ENS), disruption of the modulation of the ENS by extrinsic innervation as present in many patients with SB and SCI might lead to motility disorders. In order to gain insight in the pathophysiology, we studied histological changes of the neuromuscular structures in the colon of SB and SCI patients. Archival colon tissue blocks from SB (n = 13) and SCI (n = 34) patients were collected nationwide in The Netherlands and compared with control samples (n = 16). Histological (semiquantitative) evaluation of the ENS, the network of interstitial cells of Cajal (ICC), and the muscularis propria was performed using hematoxylin and eosin, periodic acid Schiff, and elastic von Gieson staining, and immunohistochemistry with antibodies against HuC/D, calretinin, S100, CD117, α-smooth muscle actin, and desmin. Compared to controls, SB and SCI patients showed neuronal loss and decreased nerve fiber density in the myenteric plexus. Lower nerve fiber density was significantly more often found in patients with severe bowel dysfunction. Other major findings were loss of ICCs around the myenteric plexus and fibrosis in the longitudinal muscle layer. Altered histology of the ENS may explain abnormal intestinal motility in SB and SCI patients. Furthermore, loss of myenteric nerve fibers (including enteric glial cells) may play a major role in the development of severe motility complaints.
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Affiliation(s)
- Marjanne den Braber-Ymker
- Department of Pathology, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.
| | - Martin Lammens
- Department of Pathology, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands
- Department of Pathology, Antwerp University Hospital, University of Antwerp, Edegem, Belgium
- MIPRO, University of Antwerp, Antwerp, Belgium
| | - Michel J A M van Putten
- Department of Clinical Neurophysiology, MIRA, Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede, The Netherlands
- Department of Neurology and Clinical Neurophysiology, Medisch Spectrum Twente, Enschede, The Netherlands
| | - Iris D Nagtegaal
- Department of Pathology, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands
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Gevaert T, Ridder DD, Vanstreels E, Daelemans D, Everaerts W, Aa FVD, Pintelon I, Timmermans JP, Roskams T, Steiner C, Neuhaus J. The stem cell growth factor receptor KIT is not expressed on interstitial cells in bladder. J Cell Mol Med 2016; 21:1206-1216. [PMID: 27997763 PMCID: PMC5431123 DOI: 10.1111/jcmm.13054] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Accepted: 11/10/2016] [Indexed: 01/28/2023] Open
Abstract
The mast/stem cell growth factor receptor KIT has long been assumed to be a specific marker for interstitial cells of Cajal (ICC) in the bladder, with possible druggable perspectives. However, several authors have challenged the presence of KIT+ICC in recent years. The aim of this study was therefore to attempt to clarify the conflicting reports on KIT expression in the bladder of human beings, rat, mouse and guinea pig and to elucidate the possible role of antibody‐related issues and interspecies differences in this matter. Fresh samples were obtained from human, rat, mouse and guinea pig cystectomies and processed for single/double immunohistochemistry/immunofluorescence. Specific antibodies against KIT, mast cell tryptase (MCT), anoctamin‐1 (ANO1) and vimentin were used to characterize the cell types expressing KIT. Gut (jejunum) tissue was used as an external antibody control. Our results revealed KIT expression on mast cells but not on ICC in human, rat, mouse and guinea pig bladder. Parallel immunohistochemistry showed KIT expression on ICC in human, rat, mouse and guinea pig gut, which confirmed the selectivity of the KIT antibody clones. In conclusion, we have shown that KIT+ cells in human, rat, mouse and guinea pig bladder are mast cells and not ICC. The present report is important as it opposes the idea that KIT+ICC are present in bladder. In this perspective, functional concepts of KIT+ICC being involved in sensory and/or motor aspects of bladder physiology should be revised.
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Affiliation(s)
- Thomas Gevaert
- Laboratory of Experimental Urology, Organ Systems, KU Leuven, Leuven, Belgium.,Translational Cell and Tissue Research, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium.,Department of Pathology, AZ Klina, Brasschaat, Belgium
| | - Dirk De Ridder
- Laboratory of Experimental Urology, Organ Systems, KU Leuven, Leuven, Belgium.,Department of Urology, UZ Leuven, Leuven, Belgium
| | - Els Vanstreels
- Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
| | - Dirk Daelemans
- Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
| | - Wouter Everaerts
- Laboratory of Experimental Urology, Organ Systems, KU Leuven, Leuven, Belgium.,Department of Urology, UZ Leuven, Leuven, Belgium
| | - Frank Van Der Aa
- Laboratory of Experimental Urology, Organ Systems, KU Leuven, Leuven, Belgium.,Department of Urology, UZ Leuven, Leuven, Belgium
| | - Isabel Pintelon
- Department of Veterinary Sciences, University of Antwerp, Antwerp, Belgium
| | | | - Tania Roskams
- Translational Cell and Tissue Research, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium
| | - Clara Steiner
- Klinik und Poliklinik für Urologie, University of Leipzig, Leipzig, Germany
| | - Jochen Neuhaus
- Klinik und Poliklinik für Urologie, University of Leipzig, Leipzig, Germany
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Tekin A, Karakuş OZ, Hakgüder G, Ateş O, Özer E, Olguner M, Akgür FM. Distribution of interstitial cells of Cajal in the bladders of fetal rats with retinoic acid induced myelomeningocele. Turk J Urol 2016; 42:285-289. [PMID: 27909623 DOI: 10.5152/tud.2016.98474] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
OBJECTIVE Myelomeningocele (MMC) is one of the most common reason of neurogenic bladder dysfunction in children. Although neurogenic bladder dysfunction occurrence is related with bladder innervation, also there are some changes seen in the smooth muscle and neural cells of the bladder. Interstitial cells of Cajal (ICC) are the pacemaker cells found in organs with peristaltic activity. Although it has been shown that ICC are diminished in the rat urinary bladder with traumatic spinal cord injury, there is no data about ICC in fetal rat bladders with MMC. This study has been conducted to investigate the ICC in the bladders of fetal rats with retinoic acid induced MMC. MATERIALS AND METHODS Time dated pregnant Wistar albino rats were divided into 3 groups. In MMC group, dams were fed with gavage solution containing 60 mg/kg all-trans retinoic acid dissolved in olive oil on 10. embryologic day. Sham group animals were fed only olive oil. Control group dams were fed with standard rat chow. Fetuses were delivered by cesarean section and harvested on 22. embryologic day. MMC was identified by observing MMC sacs at the back of the fetuses. Distribution of ICCs were evaluated using immunohistochemical staining. RESULTS ICCs were found in all groups, which have the same morphological features that had been described earlier in the gastrointestinal tract and the bladder. The density of the ICC in the MMC group was found to be significantly decreased when compared with the control and the sham groups (p<0.05). CONCLUSION The density of the ICC in the urinary bladder decreased in the neurogenic bladder developed in MMC.
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Affiliation(s)
- Ali Tekin
- Departments of Pediatric Surgery, Section of Pediatric Urology, Ege University School of Medicine, İzmir, Turkey
| | - Osman Zeki Karakuş
- Departments of Pediatric Surgery, Dokuz Eylül University School of Medicine, İzmir, Turkey
| | - Gülce Hakgüder
- Departments of Pediatric Surgery, Dokuz Eylül University School of Medicine, İzmir, Turkey
| | - Oğuz Ateş
- Departments of Pediatric Surgery, Dokuz Eylül University School of Medicine, İzmir, Turkey
| | - Erdener Özer
- Departments of Pathology, Dokuz Eylül University School of Medicine, İzmir, Turkey
| | - Mustafa Olguner
- Departments of Pediatric Surgery, Dokuz Eylül University School of Medicine, İzmir, Turkey
| | - Feza Miraç Akgür
- Departments of Pediatric Surgery, Dokuz Eylül University School of Medicine, İzmir, Turkey
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Abstract
Ineffective esophageal motility (IEM) is characterized by low to very low amplitude propulsive contractions in the distal esophagus, hence primarily affecting the smooth muscle part of the esophagus. IEM is often found in patients with dysphagia or heartburn and is commonly associated with gastroesophageal reflux disease. IEM is assumed to be associated with ineffective bolus transport; however, this can be verified using impedance measurements or evaluation of a barium coated marshmallow swallow. Furthermore, water swallows may not assess accurately the motor capabilities of the esophagus, since contraction amplitude is strongly determined by the size and consistency of the bolus. The “peristaltic reserve” of the esophagus can be evaluated by multiple rapid swallows that, after a period of diglutative inhibition, normally give a powerful peristaltic contraction suggestive of the integrity of neural orchestration and smooth muscle action. The amplitude of contraction is determined by a balance between intrinsic excitatory cholinergic, inhibitory nitrergic, as well as postinhibition rebound excitatory output to the musculature. This is strongly influenced by vagal efferent motor neurons and this in turn is influenced by vagal afferent neurons that send bolus information to the solitary nucleus where programmed activation of the vagal motor neurons to the smooth muscle esophagus is initiated. Solitary nucleus activity is influenced by sensory activity from a large number of organs and various areas of the brain, including the hypothalamus and the cerebral cortex. This allows interaction between swallowing activities and respiratory and cardiac activities and allows the influence of acute and chronic emotional states on swallowing behavior. Interstitial cells of Cajal are part of the sensory units of vagal afferents, the intramuscular arrays, and they provide pacemaker activity to the musculature that can generate peristalsis in the absence of innervation. This indicates that a low-amplitude esophageal contraction, observed as IEM, can be caused by a multitude of factors, and therefore many pathways can be potentially explored to restore normal esophageal peristalsis.
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Affiliation(s)
- Ji-Hong Chen
- Department of Gastroenterology, Renmin Hospital, Wuhan University, Wuhan, People's Republic of China; Division of Gastroenterology, Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
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den Braber-Ymker M, Heijker S, Lammens M, Nagtegaal ID. Practical and reproducible estimation of myenteric interstitial cells of Cajal in the bowel for diagnostic purposes. Neurogastroenterol Motil 2016; 28:1261-7. [PMID: 27037543 DOI: 10.1111/nmo.12831] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2015] [Accepted: 03/07/2016] [Indexed: 02/08/2023]
Abstract
BACKGROUND Histological assessment of the interstitial cells of Cajal (ICCs) in the bowel is important for diagnosing patients with gastrointestinal neuromuscular diseases (GINMD). Although the International Working Group on GINMD proposed reporting a decrease in ICC number of more than 50%, quantitative methods used in literature are not practical for daily routine of the pathologist. Consequently, this study presents a straightforward semiquantitative estimation method for myenteric ICCs of the bowel. METHODS Formalin-fixed paraffin-embedded sections from small bowel (n = 87) and colon (n = 159) were collected to create two control groups and four groups composed of patients with gastrointestinal motility disorders. The control groups included material of resection and autopsy origin, respectively. Samples were stained with CD117 (c-kit) antibody to estimate the myenteric ICC network. Scores of two observers were compared to analyze inter- and intraobserver agreement and reliability. KEY RESULTS Interobserver reliability was almost perfect for small bowel (intraclass correlation coefficient 0.847; 95% confidence interval [CI]: 0.774-0.897) and substantial for colon (0.683; 95% CI: 0.591-0.758). Almost perfect intraobserver reliability was found (intraclass correlation coefficient 0.918; 95% CI: 0.874-0.947). The small bowel showed more myenteric ICCs than the colon. Neither significant differences between colonic regions were found nor were there any differences in the orientation of the sections. CONCLUSIONS & INFERENCES The proposed estimation method for the myenteric ICC network showed generally good agreement and reliability. As the method is semiquantitative, simple, and capable to differentiate between normal and diseased tissue, it can be used in routine diagnostics of gastrointestinal neuromuscular disorders.
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Affiliation(s)
- M den Braber-Ymker
- Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - S Heijker
- Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - M Lammens
- Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands.,Department of Pathology, Antwerp University Hospital, University of Antwerp, Edegem, Belgium.,MIPRO, University of Antwerp, Antwerp, Belgium
| | - I D Nagtegaal
- Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands
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Karakuş OZ, Ulusoy O, Aktürk G, Ateş O, Olgun EG, Dalgıç M, Hakgüder G, Özer E, Olguner M, Akgür FM. The Density of Interstitial Cells of Cajal Is Diminished in Choledochal Cysts. Dig Dis Sci 2016; 61:900-4. [PMID: 26547756 DOI: 10.1007/s10620-015-3936-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2015] [Accepted: 10/22/2015] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIMS Interstitial cells of Cajal (ICC) have been shown to be present in the extrahepatic biliary tract of animals and humans. However, ICC distribution in choledochal cysts (CC) has not been investigated. A study was conducted to investigate the distribution of ICC in the extrahepatic biliary tract, including CC, in pediatric human specimens. METHOD The specimens were divided into two main groups as gallbladders and common bile ducts. Gallbladders were obtained from the cholelithiasis, CC operations and autopsies. Common bile ducts were obtained from autopsies. Tissues were stained using c-kit immunohistochemical staining. ICC were assessed semi-quantitatively by applying morphological criteria and were counted as the number of cells/0.24 mm(2) in each area under light microscopy. RESULTS A total of 35 gallbladders and 14 CC were obtained from operations. Ten gallbladders plus common bile ducts were obtained from autopsies. The mean numbers of ICC in the gallbladders of cholelithiasis and the gallbladders of CC were 12.2 ± 4.9 and 5.3 ± 1.2, respectively (p = 0.003). The mean numbers of ICC in the common bile ducts and CC were 9.8 ± 2.9 and 3.4 ± 1.4, respectively (p = 0.001). CONCLUSION The scarcity of ICC in the extrahepatic biliary tract may be responsible for the etiopathogenesis of the CC.
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Affiliation(s)
- Osman Z Karakuş
- Department of Pediatric Surgery, Dokuz Eylül University, Medical School, Izmir, Turkey. .,Çocuk Cerrahisi Anabilim Dalı, Tıp Fakültesi, Dokuz Eylül Üniversitesi, 35340, Balçova, Izmir, Turkey.
| | - Oktay Ulusoy
- Department of Pediatric Surgery, Dokuz Eylül University, Medical School, Izmir, Turkey
| | - Güray Aktürk
- Department of Pathology, Dokuz Eylül University, Medical School, Izmir, Turkey
| | - Oğuz Ateş
- Department of Pediatric Surgery, Dokuz Eylül University, Medical School, Izmir, Turkey
| | - Esra G Olgun
- Department of Morgue, Regional Center, Forensic Medicine Institutions, Izmir, Turkey
| | - Mustafa Dalgıç
- Department of Morgue, Regional Center, Forensic Medicine Institutions, Izmir, Turkey
| | - Gülce Hakgüder
- Department of Pediatric Surgery, Dokuz Eylül University, Medical School, Izmir, Turkey
| | - Erdener Özer
- Department of Pathology, Dokuz Eylül University, Medical School, Izmir, Turkey
| | - Mustafa Olguner
- Department of Pediatric Surgery, Dokuz Eylül University, Medical School, Izmir, Turkey
| | - Feza M Akgür
- Department of Pediatric Surgery, Dokuz Eylül University, Medical School, Izmir, Turkey
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Paracrine Signaling in the Prostatic Stroma: A Novel Role for the Telocytes Revealed in Rodents’ Ventral Prostate. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 913:193-206. [DOI: 10.1007/978-981-10-1061-3_13] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Gao J, Du P, O'Grady G, Archer R, Gibbons SJ, Farrugia G, Cheng LK. Cellular automaton model for simulating tissue-specific intestinal electrophysiological activity. ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. ANNUAL INTERNATIONAL CONFERENCE 2015; 2013:5537-40. [PMID: 24110991 DOI: 10.1109/embc.2013.6610804] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Depletion of interstitial cell of Cajal (ICC) networks is known to occur in various gastrointestinal (GI) motility disorders. Although techniques for quantifying the structure of ICC networks are available, the ICC network structure-function relationships are yet to be well elucidated. Existing methods of relating ICC structure to function are computationally expensive, and it is difficult to up-scale them to larger multiscale simulations. A new cellular automaton model for simulating tissue-specific slow wave propagation was developed, and in preliminary studies the automaton model was applied on jejunal ICC network structures from wild-type and 5-HT2B receptor knockout (ICC depleted) mice. Two metrics were also developed to quantify the simulated propagation patterns: 1) ICC and 2) non-ICC activation lag metrics. These metrics measured the average delay in time taken for the slow wave to propagate across the ICC and non-ICC domain throughout the entire network compared to the theoretical fastest propagation, respectively. Slow wave propagation was successfully simulated across the ICC networks with greatly reduced computational time compared to previous methods, and the propagation pattern metrics quantitatively revealed an impaired propagation during ICC depletion. In conclusion, the developed slow wave propagation model and propagation pattern metrics offer a computationally efficient framework for relating ICC structure to function. These tools can now be further applied to define ICC structure-function relationships across various spatial and temporal scales.
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Zani-Ruttenstock E, Zani A, Paul A, Diaz-Cano S, Ade-Ajayi N. Interstitial cells of Cajal are decreased in patients with gastroschisis associated intestinal dysmotility. J Pediatr Surg 2015; 50:750-4. [PMID: 25783375 DOI: 10.1016/j.jpedsurg.2015.02.029] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2015] [Accepted: 02/13/2015] [Indexed: 01/03/2023]
Abstract
BACKGROUND Gastroschisis associated intestinal dysmotility (GAID) is poorly understood. Animal experiments suggest that interstitial cells of Cajal (ICC), play an important role. METHODS Infants with gastroschisis (GS) and GAID (time to full feed >42days) were selected. Age matched GS and control (NEC, ileal atresia, malrotation, and volvulus) samples from primary (T1) and secondary (T2) time points underwent standard histopathology and immunohistochemistry for identification of ICC, followed by evaluation of ICC numbers, distribution, morphology, relation to ganglion cells, and myenteric plexus architecture. Groups were compared using parametric and nonparametric tests. MAIN RESULTS Twelve patients had samples available for histopathological evaluation. GAID patients had a significantly lower total number of ICCs than controls (3 vs. 8, P<0.0029). ICC number at T1 was 2.5 vs. 6 (P=0.0629) and significantly lower at T2. (3.5 vs. 11, P=0.0124). GAID patients did not show a significant increase of ICC from T1 to T2. Controls showed a significant increase of ICC over time (6 vs. 11, P=0.0408). CONCLUSION Intestinal samples from infants with GAID who underwent stoma formation demonstrated fewer ICC than controls. There was no improvement or cell recovery during the study period. The ability to modulate ICC may have significant implications for the management of GAID.
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Affiliation(s)
| | - Augusto Zani
- Department of Paediatric Surgery, King's College Hospital, London, UK
| | - Anu Paul
- Department of Paediatric Surgery, King's College Hospital, London, UK
| | | | - Niyi Ade-Ajayi
- Department of Paediatric Surgery, King's College Hospital, London, UK.
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Kito Y, Mitsui R, Ward SM, Sanders KM. Characterization of slow waves generated by myenteric interstitial cells of Cajal of the rabbit small intestine. Am J Physiol Gastrointest Liver Physiol 2015; 308:G378-88. [PMID: 25540230 PMCID: PMC4346752 DOI: 10.1152/ajpgi.00308.2014] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Slow waves (slow wavesICC) were recorded from myenteric interstitial cells of Cajal (ICC-MY) in situ in the rabbit small intestine, and their properties were compared with those of mouse small intestine. Rabbit slow wavesICC consisted of an upstroke depolarization followed by a distinct plateau component. Ni(2+) and nominally Ca(2+)-free solutions reduced the rate-of-rise and amplitude of the upstroke depolarization. Replacement of Ca(2+) with Sr(2+) enhanced the upstroke component but decreased the plateau component of rabbit slow wavesICC. In contrast, replacing Ca(2+) with Sr(2+) decreased both components of mouse slow wavesICC. The plateau component of rabbit slow wavesICC was inhibited in low-extracellular-Cl(-)-concentration (low-[Cl(-)]o) solutions and by 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), an inhibitor of Cl(-) channels, cyclopiazonic acid (CPA), an inhibitor of internal Ca(2+) pumps, or bumetanide, an inhibitor of Na(+)-K(+)-2Cl(-) cotransporter (NKCC1). Bumetanide also inhibited the plateau component of mouse slow wavesICC. NKCC1-like immunoreactivity was observed mainly in ICC-MY in the rabbit small intestine. Membrane depolarization with a high-K(+) solution reduced the upstroke component of rabbit slow wavesICC. In cells depolarized with elevated external K(+), DIDS, CPA, and bumetanide blocked slow wavesICC. These results suggest that the upstroke component of rabbit slow wavesICC is partially mediated by voltage-dependent Ca(2+) influx, whereas the plateau component is dependent on Ca(2+)-activated Cl(-) efflux. NKCC1 is likely to be responsible for Cl(-) accumulation in ICC-MY. The results also suggest that the mechanism of the upstroke component differs in rabbit and mouse slow wavesICC in the small intestine.
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Affiliation(s)
- Yoshihiko Kito
- Department of Pharmacology, Faculty of Medicine, Saga University, Nabeshima, Saga, Japan; Department of Cell Physiology, Nagoya City University Medical School, Mizuho-ku, Nagoya, Japan; and
| | - Retsu Mitsui
- 2Department of Cell Physiology, Nagoya City University Medical School, Mizuho-ku, Nagoya, Japan; and
| | - Sean M. Ward
- 3Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada
| | - Kenton M. Sanders
- 3Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada
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Young J, Ozisik S, Riviere B, Shamim M. A comprehensive mathematical framework for modeling intestinal smooth muscle cell contraction with applications to intestinal edema. Math Biosci 2015; 262:206-13. [PMID: 25640870 DOI: 10.1016/j.mbs.2014.12.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2014] [Revised: 12/11/2014] [Accepted: 12/18/2014] [Indexed: 10/24/2022]
Abstract
The contraction of intestinal smooth muscle cells (ISMCs) involves many coordinated biochemical and mechanical processes. In this work, we present a framework for modeling ISMC contractility that begins with chemical models of calcium dynamics, continues with myosin light chain phosphorylation and force generation, and ends with a cell model of the ISMC undergoing contraction-relaxation. The motivation for developing this comprehensive framework is to study the effects of edema (excess fluid build-up in the muscle tissue) on ISMC contractility. The hypothesis is that more fluid equates to dilution of an external stimulis, eventually leading to reduced contractility. We compare our results to experimental data collected from normal versus edematous intestinal muscle tissue.
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Affiliation(s)
- Jennifer Young
- Computational and Applied Mathematics Department, Rice University, Houston, Texas 77005, USA
| | - Sevtap Ozisik
- Computational and Applied Mathematics Department, Rice University, Houston, Texas 77005, USA.
| | - Beatrice Riviere
- Computational and Applied Mathematics Department, Rice University, Houston, Texas 77005, USA
| | - Muhammad Shamim
- Computational and Applied Mathematics Department, Rice University, Houston, Texas 77005, USA
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Jabari S, da Silveira ABM, de Oliveira EC, Quint K, Wirries A, Neuhuber W, Brehmer A. Interstitial cells of Cajal: crucial for the development of megacolon in human Chagas' disease? Colorectal Dis 2014; 15:e592-8. [PMID: 23810202 DOI: 10.1111/codi.12331] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2013] [Accepted: 03/02/2013] [Indexed: 02/08/2023]
Abstract
AIM Megacolon, chronic dilation of a colonic segment,is accompanied by extensive myenteric neuron loss. However, this fails to explain unequivocally the formation of megacolon. We aimed to study further enteric structures that are directly or indirectly involved in colonic motility. METHOD From surgically removed megacolon segments of seven Chagasic patients, three sets of cryosections from oral, megacolonic and anal zones were immunohistochemically quadruple-stained for smooth-muscle actin (SMA), synaptophysin (SYN, for nerve fibres), S100 (glia) and c-Kit (interstitial cells of Cajal, ICCs). Values of area measurements were related to the appropriate muscle layer areas and these proportions were compared with those of seven non-Chagasic control patients. RESULTS Whereas nerve and glia profile proportions did not mirror unequivocally the changes of Chagasic colon calibre (nondilation/dilation/nondilation), the proportions of SMA (i.e. muscle tissue density) and c-Kit (i.e. ICC density) did so: they decreased from the oral to the megacolonic segment but increased to the anal zones (muscle tissue density: control 68.3%, oral 54.3%, mega 42.1%, anal 47.6%; ICC-density: control 1.8%, oral 1.1%, mega 0.4, anal 0.8%). CONCLUSION Of the parameters evaluated, muscle tissue and ICC densities may be involved in the formation of Chagasic megacolon, although the mechanism of destruction cannot be deduced.
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Affiliation(s)
- S Jabari
- Institute of Anatomy I, University of Erlangen-Nuremberg, Erlangen, Germany
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Youm JB, Leem CH, Lee SR, Song IS, Kim HK, Heo HJ, Kim BJ, Kim N, Han J. Modeling of stochastic behavior of pacemaker potential in interstitial cells of Cajal. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2014; 116:56-69. [PMID: 25238716 DOI: 10.1016/j.pbiomolbio.2014.09.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/26/2014] [Revised: 08/28/2014] [Accepted: 09/06/2014] [Indexed: 01/20/2023]
Abstract
It is widely accepted that interstitial cells of Cajal (ICCs) generate pacemaker potentials to propagate slow waves along the whole gastrointestinal tract. Previously, we constructed a biophysically based model of ICCs in mouse small intestine to explain the pacemaker mechanism. Our previous model, however, could not explain non-uniformity of pacemaker potentials and random occurrence of unitary potentials, thus we updated our model. The inositol 1,4,5-trisphosphate (IP3)-mediated Ca(2+) mobilization is a key event to drive the cycle of pacemaker activity and was updated to reproduce its stochastic behavior. The stochasticity was embodied by simulating random opening and closing of individual IP3-mediated Ca(2+) channel. The updated model reproduces the stochastic features of pacemaker potentials in ICCs. Reproduced pacemaker potentials are not uniform in duration and interval. The resting and peak potentials are -75.5 ± 1.1 mV and -0.8 ± 0.5 mV, respectively (n = 55). Frequency of pacemaker potential is 14.3 ± 0.4 min(-1) (n = 10). Width at half-maximal amplitude of pacemaker potential is 902 ± 6 ms (n = 55). There are random events of unitary potential-like depolarization. Finally, we compared our updated model with a recently published model to speculate which ion channel is the best candidate to drive pacemaker depolarization. In conclusion, our updated mathematical model could now reproduce stochastic features of pacemaker activity in ICCs.
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Affiliation(s)
- Jae Boum Youm
- Department of Physiology, College of Medicine, Cardiovascular and Metabolic Disease Center, Inje University, Busan, South Korea.
| | - Chae Hun Leem
- Department of Physiology University of Ulsan College of Medicine, Seoul, South Korea
| | - Sung Ryul Lee
- Department of Physiology, College of Medicine, Cardiovascular and Metabolic Disease Center, Inje University, Busan, South Korea
| | - In-Sung Song
- Department of Physiology, College of Medicine, Cardiovascular and Metabolic Disease Center, Inje University, Busan, South Korea
| | - Hyoung Kyu Kim
- Department of Physiology, College of Medicine, Cardiovascular and Metabolic Disease Center, Inje University, Busan, South Korea
| | - Hye Jin Heo
- Department of Physiology, College of Medicine, Cardiovascular and Metabolic Disease Center, Inje University, Busan, South Korea
| | - Byung Joo Kim
- Division of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine, Yangsan, South Korea
| | - Nari Kim
- Department of Physiology, College of Medicine, Cardiovascular and Metabolic Disease Center, Inje University, Busan, South Korea
| | - Jin Han
- Department of Physiology, College of Medicine, Cardiovascular and Metabolic Disease Center, Inje University, Busan, South Korea
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Haller F, Zhang JD, Moskalev EA, Braun A, Otto C, Geddert H, Riazalhosseini Y, Ward A, Balwierz A, Schaefer IM, Cameron S, Ghadimi BM, Agaimy A, Fletcher JA, Hoheisel J, Hartmann A, Werner M, Wiemann S, Sahin Ö. Combined DNA methylation and gene expression profiling in gastrointestinal stromal tumors reveals hypomethylation ofSPP1as an independent prognostic factor. Int J Cancer 2014; 136:1013-23. [DOI: 10.1002/ijc.29088] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2014] [Accepted: 07/03/2014] [Indexed: 02/05/2023]
Affiliation(s)
- Florian Haller
- Institute of Pathology; Friedrich Alexander University; Erlangen-Nuremberg Germany
| | - Jitao David Zhang
- Division of Molecular Genome Analysis; German Cancer Research Center; Heidelberg Germany
| | - Evgeny A. Moskalev
- Institute of Pathology; Friedrich Alexander University; Erlangen-Nuremberg Germany
| | - Alexander Braun
- Institute of Pathology; Albert Ludwigs University; Freiburg Germany
| | - Claudia Otto
- Institute of Pathology; Albert Ludwigs University; Freiburg Germany
| | - Helene Geddert
- Institute of Pathology; St. Vincentius Hospital; Karlsruhe Germany
| | - Yasser Riazalhosseini
- Division of Functional Genome Analysis; German Cancer Research Center; Heidelberg Germany
| | - Aoife Ward
- Division of Molecular Genome Analysis; German Cancer Research Center; Heidelberg Germany
| | - Aleksandra Balwierz
- Division of Molecular Genome Analysis; German Cancer Research Center; Heidelberg Germany
| | | | - Silke Cameron
- Department of Gastroenterology and Endocrinology; Georg August University; Göttingen Germany
| | - B. Michael Ghadimi
- Department of General and Visceral Surgery; Georg August University; Göttingen Germany
| | - Abbas Agaimy
- Institute of Pathology; Friedrich Alexander University; Erlangen-Nuremberg Germany
| | | | - Jörg Hoheisel
- Division of Functional Genome Analysis; German Cancer Research Center; Heidelberg Germany
| | - Arndt Hartmann
- Institute of Pathology; Friedrich Alexander University; Erlangen-Nuremberg Germany
| | - Martin Werner
- Institute of Pathology; Albert Ludwigs University; Freiburg Germany
| | - Stefan Wiemann
- Division of Molecular Genome Analysis; German Cancer Research Center; Heidelberg Germany
- Genomics and Proteomics Core Facility; German Cancer Research Center; Heidelberg Germany
| | - Özgür Sahin
- Division of Molecular Genome Analysis; German Cancer Research Center; Heidelberg Germany
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Blair PJ, Rhee PL, Sanders KM, Ward SM. The significance of interstitial cells in neurogastroenterology. J Neurogastroenterol Motil 2014; 20:294-317. [PMID: 24948131 PMCID: PMC4102150 DOI: 10.5056/jnm14060] [Citation(s) in RCA: 97] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2014] [Revised: 06/06/2014] [Accepted: 06/07/2014] [Indexed: 12/21/2022] Open
Abstract
Smooth muscle layers of the gastrointestinal tract consist of a heterogeneous population of cells that include enteric neurons, several classes of interstitial cells of mesenchymal origin, a variety of immune cells and smooth muscle cells (SMCs). Over the last number of years the complexity of the interactions between these cell types has begun to emerge. For example, interstitial cells, consisting of both interstitial cells of Cajal (ICC) and platelet-derived growth factor receptor alpha-positive (PDGFRα(+)) cells generate pacemaker activity throughout the gastrointestinal (GI) tract and also transduce enteric motor nerve signals and mechanosensitivity to adjacent SMCs. ICC and PDGFRα(+) cells are electrically coupled to SMCs possibly via gap junctions forming a multicellular functional syncytium termed the SIP syncytium. Cells that make up the SIP syncytium are highly specialized containing unique receptors, ion channels and intracellular signaling pathways that regulate the excitability of GI muscles. The unique role of these cells in coordinating GI motility is evident by the altered motility patterns in animal models where interstitial cell networks are disrupted. Although considerable advances have been made in recent years on our understanding of the roles of these cells within the SIP syncytium, the full physiological functions of these cells and the consequences of their disruption in GI muscles have not been clearly defined. This review gives a synopsis of the history of interstitial cell discovery and highlights recent advances in structural, molecular expression and functional roles of these cells in the GI tract.
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Affiliation(s)
- Peter J Blair
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV, USA; and
| | - Poong-Lyul Rhee
- Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Kenton M Sanders
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV, USA; and
| | - Sean M Ward
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV, USA; and
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Abstract
Megacolon, the irreversible dilation of a colonic segment, is a structural sign associated with various gastrointestinal disorders. In its hereditary, secondary form (e.g. in Hirschsprung's disease), dilation occurs in an originally healthy colonic segment due to an anally located, aganglionic zone. In contrast, in chronic Chagas' disease, the dilated segment itself displays pathohistological changes, and the earliest and most prominent being found was massive loss of myenteric neurons. This neuron loss was partial and selective, i.e. some neurons containing neuronal nitric oxide synthase and/or vasoactive intestinal peptide (VIP) were spared from neuron death. This disproportionate survival of inhibitory neurons, however, did not completely correlate with the calibre change along the surgically removed, megacolonic segments. A better correlation was observed as to potentially contractile muscle tissue elements and the interstitial cells of Cajal. Therefore, the decreased densities of α-smooth muscle actin- and c-kit-immunoreactive profiles were estimated along resected megacolonic segments. Their lowest values were observed in the megacolonic zones itself, whereas less pronounced decreases were found in the non-dilated, transitional zones (oral and anal to dilation). In contrast to the myenteric plexus, the submucosal plexus displayed only a moderate neuron loss. Neurons co-immunoreactive for VIP and calretinin survived disproportionately. As a consequence, these neurons may have contributed to maintain the epithelial barrier and allowed the chagasic patients to survive for decades, despite their severe disturbance of colonic motility. Due to its neuroprotective and neuroeffectory functions, VIP may play a key role in the development and duration of chagasic megacolon.
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