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Xu H, Miao F, Fan Y. A bibliometric analysis of diabetic gastroparesis from 1979 to 2024. Front Med (Lausanne) 2024; 11:1445276. [PMID: 39450111 PMCID: PMC11500038 DOI: 10.3389/fmed.2024.1445276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Accepted: 09/09/2024] [Indexed: 10/26/2024] Open
Abstract
Objective Gastroparesis is one of the complications of diabetes mellitus, which has a major impact on the quality of life of patients, and the limited therapeutic options currently available make it a public health problem. No bibliometric studies on diabetic gastroparesis have been published to date. Therefore, the aim of this paper is to summarize and analyze the research hotspots for researchers. Methods Research articles related to Diabetic gastroparesis were searched in Web of Science Core Collection (WOSCC), and relevant information was extracted after screening. A comprehensive bibliometric analysis of 699 publications was conducted using Microsoft Excel 2019, Citespace and VOSviewers. Result A total of 699 papers from 738 institutions in 41 countries were retrieved. Publications in this field have increased rapidly since 1979. USA (n = 370) and Mayo Clinical (n = 69) were the most productive country and institution, respectively. Neurogastroenterology and Motility (n = 67) was the most published journal with Parkman, Henry P. (n = 40) having the highest number of articles; Gastroenterology and Mccallum, Richard W. were the most influential journals and authors. Conclusions The research hotspots of Diabetic gastroparesis are mainly focused on treatment modalities and pathological mechanisms. Future research in diabetic gastroparesis will focus on exploring the pathomechanisms, finding long-term effective treatments, and improving patients' quality of life.
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Affiliation(s)
| | | | - Yushan Fan
- College of Acupuncture-Moxibustion and Tuina, Guangxi University of Chinese Medicine, Nanning, China
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2
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Dershowitz LB, Kaltschmidt JA. Enteric Nervous System Striped Patterning and Disease: Unexplored Pathophysiology. Cell Mol Gastroenterol Hepatol 2024; 18:101332. [PMID: 38479486 PMCID: PMC11176954 DOI: 10.1016/j.jcmgh.2024.03.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 03/08/2024] [Accepted: 03/08/2024] [Indexed: 04/04/2024]
Abstract
The enteric nervous system (ENS) controls gastrointestinal (GI) motility, and defects in ENS development underlie pediatric GI motility disorders. In disorders such as Hirschsprung's disease (HSCR), pediatric intestinal pseudo-obstruction (PIPO), and intestinal neuronal dysplasia type B (INDB), ENS structure is altered with noted decreased neuronal density in HSCR and reports of increased neuronal density in PIPO and INDB. The developmental origin of these structural deficits is not fully understood. Here, we review the current understanding of ENS development and pediatric GI motility disorders incorporating new data on ENS structure. In particular, emerging evidence demonstrates that enteric neurons are patterned into circumferential stripes along the longitudinal axis of the intestine during mouse and human development. This novel understanding of ENS structure proposes new questions about the pathophysiology of pediatric GI motility disorders. If the ENS is organized into stripes, could the observed changes in enteric neuron density in HSCR, PIPO, and INDB represent differences in the distribution of enteric neuronal stripes? We review mechanisms of striped patterning from other biological systems and propose how defects in striped ENS patterning could explain structural deficits observed in pediatric GI motility disorders.
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Affiliation(s)
- Lori B Dershowitz
- Department of Neurosurgery, Stanford University School of Medicine, Stanford, California; Wu Tsai Neurosciences Institute, Stanford University, Stanford, California
| | - Julia A Kaltschmidt
- Department of Neurosurgery, Stanford University School of Medicine, Stanford, California; Wu Tsai Neurosciences Institute, Stanford University, Stanford, California.
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3
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Dershowitz LB, Li L, Pasca AM, Kaltschmidt JA. Anatomical and functional maturation of the mid-gestation human enteric nervous system. Nat Commun 2023; 14:2680. [PMID: 37160892 PMCID: PMC10170115 DOI: 10.1038/s41467-023-38293-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 04/14/2023] [Indexed: 05/11/2023] Open
Abstract
Immature gastrointestinal motility impedes preterm infant survival. The enteric nervous system controls gastrointestinal motility, yet it is unknown when the human enteric nervous system matures enough to carry out vital functions. Here we demonstrate that the second trimester human fetal enteric nervous system takes on a striped organization akin to the embryonic mouse. Further, we perform ex vivo functional assays of human fetal tissue and find that human fetal gastrointestinal motility matures in a similar progression to embryonic mouse gastrointestinal motility. Together, this provides critical knowledge, which facilitates comparisons with common animal models to advance translational disease investigations and testing of pharmacological agents to enhance gastrointestinal motility in prematurity.
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Affiliation(s)
- Lori B Dershowitz
- Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, 94305, USA
- Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, 94305, USA
| | - Li Li
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, 94305, USA
| | - Anca M Pasca
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, 94305, USA.
| | - Julia A Kaltschmidt
- Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, 94305, USA.
- Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, 94305, USA.
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4
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Friedmacher F, Rolle U. Interstitial cells of Cajal: clinical relevance in pediatric gastrointestinal motility disorders. Pediatr Surg Int 2023; 39:188. [PMID: 37101012 PMCID: PMC10133055 DOI: 10.1007/s00383-023-05467-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/03/2023] [Indexed: 04/28/2023]
Abstract
Interstitial cells of Cajal (ICCs) are pacemaker cells of gastrointestinal motility that generate and transmit electrical slow waves to smooth muscle cells in the gut wall, thus inducing phasic contractions and coordinated peristalsis. Traditionally, tyrosine-protein kinase Kit (c-kit), also known as CD117 or mast/stem cell growth factor receptor, has been used as the primary marker of ICCs in pathology specimens. More recently, the Ca2+-activated chloride channel, anoctamin-1, has been introduced as a more specific marker of ICCs. Over the years, various gastrointestinal motility disorders have been described in infants and young children in which symptoms of functional bowel obstruction arise from ICC-related neuromuscular dysfunction of the colon and rectum. The current article provides a comprehensive overview of the embryonic origin, distribution, and functions of ICCs, while also illustrating the absence or deficiency of ICCs in pediatric patients with Hirschsprung disease intestinal neuronal dysplasia, isolated hypoganglionosis, internal anal sphincter achalasia, and congenital smooth muscle cell disorders such as megacystis microcolon intestinal hypoperistalsis syndrome.
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Affiliation(s)
- Florian Friedmacher
- Department of Paediatric Surgery and Paediatric Urology, University Hospital Frankfurt, Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany
| | - Udo Rolle
- Department of Paediatric Surgery and Paediatric Urology, University Hospital Frankfurt, Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany.
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5
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Yagasaki R, Shikaya Y, Kawachi T, Inaba M, Takase Y, Takahashi Y. Newly raised anti-c-Kit antibody visualizes morphology of interstitial cells of Cajal in the developing gut of chicken embryos. Dev Growth Differ 2022; 64:446-454. [PMID: 36069474 DOI: 10.1111/dgd.12808] [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: 05/31/2022] [Revised: 08/25/2022] [Accepted: 08/26/2022] [Indexed: 11/28/2022]
Abstract
The gut peristaltic movement, a wave-like propagation of a local contraction, is important for the transportation and digestion of ingested materials. Among three types of cells, the enteric nervous system (ENS), smooth muscle cells, and interstitial cells of Cajal (ICCs), the ICCs have been thought to act as a pacemaker, and therefore it is important to decipher the cellular functions of ICCs for the understanding of gut peristalsis. c-Kit, a tyrosine kinase receptor, has widely been used as a marker for ICCs. Most studies with ICCs have been conducted in mammals using commercially available anti-c-Kit antibody. Recently, the chicken embryonic gut has emerged as a powerful model to study the gut peristalsis. However, since the anti-c-Kit antibody for mammals does not work for chickens, cellular mechanisms by which ICCs are regulated have largely been unexplored. Here, we report a newly raised polyclonal antibody against the chicken c-Kit protein. The specificity of the antibody was validated by both Western blotting analyses and immunocytochemistry. Co-immunostaining with the new antibody and anti-α smooth muscle actin (αSMA) antibody successfully visualized ICCs in the chicken developing hindgut in the circular muscle- and longitudinal muscle layers: as previously shown in mice, common progenitors of ICCs and smooth muscle cells at early stages were double positive for αSMA and c-Kit, and at later stages, differentiated ICCs and smooth muscle cells exhibited only c-Kit and αSMA, respectively. A novel ICC population was also found that radially extended from the submucosal layer to circular muscle layer. Furthermore, the new antibody delineated individual ICCs in a cleared hindgut. The antibody newly developed in this study will facilitate the study of peristaltic movement in chicken embryos.
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Affiliation(s)
- Rei Yagasaki
- Department of Zoology, Graduate School of Science, Kyoto University Sakyo-ku, Kyoto
| | - Yuuki Shikaya
- Department of Zoology, Graduate School of Science, Kyoto University Sakyo-ku, Kyoto
| | - Teruaki Kawachi
- Department of Zoology, Graduate School of Science, Kyoto University Sakyo-ku, Kyoto
| | - Masafumi Inaba
- Department of Zoology, Graduate School of Science, Kyoto University Sakyo-ku, Kyoto
| | - Yuta Takase
- Department of Zoology, Graduate School of Science, Kyoto University Sakyo-ku, Kyoto
| | - Yoshiko Takahashi
- Department of Zoology, Graduate School of Science, Kyoto University Sakyo-ku, Kyoto
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Terra SA, Gonçalves AC, Lourenção PLTDA, Rodrigues MAM. Challenges in the diagnosis of intestinal neuronal dysplasia type B: A look beyond the number of ganglion cells. World J Gastroenterol 2021; 27:7649-7660. [PMID: 34908804 PMCID: PMC8641051 DOI: 10.3748/wjg.v27.i44.7649] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 04/26/2021] [Accepted: 11/11/2021] [Indexed: 02/06/2023] Open
Abstract
Intestinal neuronal dysplasia type B (IND-B) is a controversial condition among gastrointestinal neuromuscular disorders. Constipation is its most common clinical manifestation in patients. Despite intense scientific research, there are still knowledge gaps regarding the diagnostic criteria for IND-B in the histopathological analysis of rectal biopsies. The guidelines published in the past three decades have directed diagnostic criteria for quantifying the number of ganglion cells in the nervous plexus of the enteric nervous system. However, it is very complex to distinguish numerically what is pathological from what is normal, mainly because of the difficulty in determining a reliable control group composed of healthy children without intestinal symptoms. Thus, a series of immunohistochemical markers have been proposed to assist in the histopathological analysis of the enteric nervous system. Several of these markers facilitate the identification of other structures of the enteric nervous system, in addition to ganglion cells. These structures may be related to the etiopathogenesis of IND-B and represent new possibilities for the histopathological diagnosis of this disease, providing a view beyond the number of ganglion cells. This review critically discusses the aspects related to the disease definitions and diagnostic criteria of this organic cause of constipation.
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Affiliation(s)
- Simone Antunes Terra
- Department of Pathology, Faculty of Medicine, São Paulo State University (UNESP), Botucatu 18618687, São Paulo, Brazil
| | - Anderson Cesar Gonçalves
- Department of Surgery and Orthopedics, Botucatu Medical School - São Paulo State University (UNESP), Botucatu 18618970, São Paulo, Brazil
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Bencomo-Loeppky S, García-Rizk JA, Cervantes-Flores HA, Levario-Carrillo M, Fierro Murga R, Reza-López SA, Loya-Loya M, Chávez-Corral DV. Neural crest derivatives and neuroendocrine cells in the gut of anencephalic and fetuses without congenital defects. Birth Defects Res 2020; 112:1720-1732. [PMID: 32914571 DOI: 10.1002/bdr2.1797] [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: 02/20/2020] [Revised: 08/03/2020] [Accepted: 08/19/2020] [Indexed: 11/09/2022]
Abstract
BACKGROUND The enteric nervous system (ENS), a component of the peripheral nervous system in the intestinal walls, regulates motility, secretion, absorption, and blood flow. Neural crest (NC) migration, fundamental for ENS development, may be altered by central nervous system development alterations, such as neural tube defects (NTD). Intestinal innervation anomalies have been correlated to NTD. We aim to describe the ENS on a fetus with NTD and fetuses without congenital defects (FWCD). CASES Two male and four female FWCD, 18-20 weeks-gestation (WG), and a 25 WG female anencephalic fetus. Samples from the pancreatoduodenal groove, jejunum, cecum, rectum, and appendix were analyzed by immunohistochemistry. Nervous plexuses were marked with Neuron-specific enolase and S-100; enteric glial cells with CD56; neuroendocrine cells with chromogranin and synaptophysin, and interstitial cells of Cajal (ICC) with CD117. RESULTS AND CONCLUSION The anencephalic fetus presented a rudimentary brainstem with a cerebellum. Partial frontal, temporal, and occipital bones were found. A large atrial septal defect, an enlarged kidney with a duplex collecting system and a single adrenal gland were found. NSE, S100, and CD56, showed the presence of the myenteric and submucous plexuses of the ENS; scarce interplexus reactivity may indicate inadequate development. Pancreatic and gut neuroendocrine cells, identified with chromogranin and CD56, showed that the enteroendocrine system is present. Findings on FWCD using these markers are consistent with literature descriptions. Vagal NC migration appears to be unaffected despite the presence of anencephaly, although maturation of the ENS may be altered.
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Affiliation(s)
- Samuel Bencomo-Loeppky
- Facultad de Medicina y Ciencias Biomédicas, Universidad Autónoma de Chihuahua, Chihuahua, Chihuahua, Mexico
| | - Jorge Arturo García-Rizk
- Facultad de Medicina y Ciencias Biomédicas, Universidad Autónoma de Chihuahua, Chihuahua, Chihuahua, Mexico
| | | | - Margarita Levario-Carrillo
- Facultad de Medicina y Ciencias Biomédicas, Universidad Autónoma de Chihuahua, Chihuahua, Chihuahua, Mexico
| | - Ricardo Fierro Murga
- Facultad de Medicina y Ciencias Biomédicas, Universidad Autónoma de Chihuahua, Chihuahua, Chihuahua, Mexico
| | - Sandra Alicia Reza-López
- Facultad de Medicina y Ciencias Biomédicas, Universidad Autónoma de Chihuahua, Chihuahua, Chihuahua, Mexico
| | - Martha Loya-Loya
- Facultad de Odontología, Universidad Autónoma de Chihuahua, Chihuahua, Chihuahua, Mexico
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8
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Radenkovic G, Radenkovic D, Velickov A. Development of interstitial cells of Cajal in the human digestive tract as the result of reciprocal induction of mesenchymal and neural crest cells. J Cell Mol Med 2017; 22:778-785. [PMID: 29193736 PMCID: PMC5783873 DOI: 10.1111/jcmm.13375] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2017] [Accepted: 08/08/2017] [Indexed: 01/02/2023] Open
Abstract
Neural crest cells (NCC) can migrate into different parts of the body and express their strong inductive potential. In addition, they are multipotent and are able to differentiate into various cell types with diverse functions. In the primitive gut, NCC induce differentiation of muscular structures and interstitial cells of Cajal (ICC), and they themselves differentiate into the elements of the enteric nervous system (ENS), neurons and glial cells. ICC develop by way of mesenchymal cell differentiation in the outer parts of the primitive gut wall around the myenteric plexus (MP) ganglia, with the exception of colon, where they appear simultaneously also at the submucosal border of the circular muscular layer around the submucosal plexus (SMP) ganglia. However, in a complex process of reciprocal induction of NCC and local mesenchyma, c‐kit positive precursors are the first to differentiate, representing probably the common precursors of ICC and smooth muscle cells (SMC). C‐kit positive precursors could represent a key impact factor regarding the final differentiation of NCC into neurons and glial cells with neurons subsequently excreting stem cell factor (SCF) and other signalling molecules. Under the impact of SCF, a portion of c‐kit positive precursors lying immediately around the ganglia differentiate into ICC, while the rest differentiate into SMC.
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Affiliation(s)
- Goran Radenkovic
- Department of Histology and Embryology, Faculty of Medicine, University of Nis, Nis, Serbia
| | - Dina Radenkovic
- UCL Medical School, University College London (UCL), London, UK
| | - Aleksandra Velickov
- Department of Histology and Embryology, Faculty of Medicine, University of Nis, Nis, Serbia
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9
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Stem Cell Factor/Kit Signal Insufficiency Contributes to Hypoxia-Induced Intestinal Motility Dysfunctions in Neonatal Mice. Dig Dis Sci 2017; 62:1193-1203. [PMID: 28315973 DOI: 10.1007/s10620-017-4533-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2016] [Accepted: 03/08/2017] [Indexed: 01/25/2023]
Abstract
BACKGROUND Gastrointestinal (GI) motility disorders represent a group of problems that more constantly encountered in preterm infants. However, whether hypoxia exposure contributes to the GI dysfunctions is still unclear. METHODS Newborn mice were exposed to hypoxia (10%) from P1 to P7. Intestinal motilities were examined by a strain gauge transducer. The proliferation of ICCs was detected by using immunostaining for BrdU, Ki67, Kit, Ano1, and insulin-like growth factor 1 receptor (IGF-1R+). Smooth muscle cells and enteric neurons were revealed by immunostaining for α-SMA and NF200, respectively. Apoptosis was assessed by TUNEL assay. Kit signal pathway was examined by western blot and qPCR. RESULTS Intestinal motilities were found weakened significantly in the hypoxic small intestines as compared to controls on P8. Kit+ or Ano1+ interstitial cells of Cajal (ICCs) were found obviously decreased in the myenteric ICCs (ICC-MY) of neonatal mice after exposed to hypoxia. A large number of ICC progenitors (IGF-1R+) were found highly mitotic (BrdU+ Ki67+) to populate ICC during early postnatal development in the normoxic mice. We found the ICC proliferation was significantly inhibited upon hypoxia exposure, without increasing apoptosis (TUNEL+). We next identified that Kit phosphorylation was inhibited 3 days after hypoxia exposure. The inhibition of Kit signaling was largely due to decreased the expression of the ligand of Kit receptor, stem cell factor (SCF), in the intestinal walls. Exposure to imatinib, a Kit receptor inhibitor, for 3 days from P4 phenocopied the effect of hypoxia on the neonatal pups that resulted in inhibited intestinal motilities and decreased Kit+ ICC numbers. CONCLUSION All together, our findings indicate the SCF/Kit signaling insufficiency may contribute to the underdevelopment of ICCs and intestinal motility dysfunction upon hypoxia exposure. The decease in ICC density is likely due to the cell cycle arrest of ICC progenitor cells.
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Ramalhosa F, Soares-Cunha C, Seixal RM, Sousa N, Carvalho AF. The Impact of Prenatal Exposure to Dexamethasone on Gastrointestinal Function in Rats. PLoS One 2016; 11:e0161750. [PMID: 27584049 PMCID: PMC5008745 DOI: 10.1371/journal.pone.0161750] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Accepted: 08/11/2016] [Indexed: 01/23/2023] Open
Abstract
Antenatal treatment with synthetic glucocorticoids is commonly used in pregnant women at risk of preterm delivery to accelerate tissue maturation. Exposure to glucocorticoids during development has been hypothesized to underlie different functional gastrointestinal (GI) and motility disorders. Herein, we investigated the impact of in utero exposure to synthetic glucocorticoids (iuGC) on GI function of adult rats. Wistar male rats, born from pregnant dams treated with dexamethasone (DEX), were studied at different ages. Length, histologic analysis, proliferation and apoptosis assays, GI transit, permeability and serotonin (5-HT) content of GI tract were measured. iuGC treatment decreased small intestine size and decreased gut transit. However, iuGC had no impact on intestinal permeability. iuGC differentially impacts the structure and function of the GI tract, which leads to long-lasting alterations in the small intestine that may predispose subjects prone to disorders of the GI tract.
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Affiliation(s)
- Fátima Ramalhosa
- Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, Braga, Portugal
- Life and Health Sciences Research Institute/Biomaterials, Biodegradables and Biometrics Associate Laboratory, Braga/Guimarães, Portugal
| | - Carina Soares-Cunha
- Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, Braga, Portugal
- Life and Health Sciences Research Institute/Biomaterials, Biodegradables and Biometrics Associate Laboratory, Braga/Guimarães, Portugal
| | - Rui Miguel Seixal
- Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, Braga, Portugal
- Life and Health Sciences Research Institute/Biomaterials, Biodegradables and Biometrics Associate Laboratory, Braga/Guimarães, Portugal
| | - Nuno Sousa
- Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, Braga, Portugal
- Life and Health Sciences Research Institute/Biomaterials, Biodegradables and Biometrics Associate Laboratory, Braga/Guimarães, Portugal
| | - Ana Franky Carvalho
- Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, Braga, Portugal
- Life and Health Sciences Research Institute/Biomaterials, Biodegradables and Biometrics Associate Laboratory, Braga/Guimarães, Portugal
- General Surgery Department, Hospital of Braga, Braga, Portugal
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11
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Gilmont RR, Raghavan S, Somara S, Bitar KN. Bioengineering of physiologically functional intrinsically innervated human internal anal sphincter constructs. Tissue Eng Part A 2014; 20:1603-11. [PMID: 24328537 DOI: 10.1089/ten.tea.2013.0422] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
Muscle replacement for patients suffering from extensive tissue loss or dysfunction is a major objective of regenerative medicine. To achieve functional status, bioengineered muscle replacement constructs require innervation. Here we describe a method to bioengineer functionally innervated gut smooth muscle constructs using neuronal progenitor cells and smooth muscle cells isolated and cultured from intestinal tissues of adult human donors. These constructs expressed markers for contractile smooth muscle, glial cells, and mature neuronal populations. The constructs responded appropriately to physiologically relevant neurotransmitters, and neural network integration was demonstrated by responses to electrical field stimulation. The ability of enteric neuroprogenitor cells to differentiate into neuronal populations provides enormous potential for functional innervation of a variety of bioengineered muscle constructs in addition to gut. Functionally innervated muscle constructs offer a regenerative medicine-based therapeutic approach for neuromuscular replacement after trauma or degenerative disorders.
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Affiliation(s)
- Robert R Gilmont
- 1 Institute for Regenerative Medicine, Wake Forest School of Medicine , Winston-Salem, North Carolina
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12
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Abramovic M, Radenkovic G, Velickov A. Appearance of interstitial cells of Cajal in the human midgut. Cell Tissue Res 2014; 356:9-14. [PMID: 24414177 DOI: 10.1007/s00441-013-1772-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2013] [Accepted: 11/14/2013] [Indexed: 12/16/2022]
Abstract
Several subtypes of the interstitial cells of Cajal (ICC) form networks that play a role in gastrointestinal motor control. ICC express c-kit and depend on signaling via Kit receptors for development and phenotype maintenance. At 7-8 weeks of development, c-kit-immunoreactive (c-kit-IR) cells are present in the human oesophagus, stomach and proximal duodenum wall. In the remaining small and large bowel, c-kit-IR cells appear later. The object of the present study is to determine the timing of the appearance of c-kit-IR ICC in the parts of the digestive tube originating from the midgut (distal duodenum, jejunum, ileum and proximal colon). Specimens were obtained from eight human embryos and 11 fetuses at 7-12 weeks of gestational age. The specimens were exposed to anti-c-kit antibodies to investigate ICC differentiation. The differentiation of enteric neurons and smooth muscle cells was immunohistochemically examined by using anti-PGP9,5 and anti-desmin antibodies, respectively. In the distal duodenum, jejunum and ileum, c-kit-IR cells emerged at week 9 at the level of the myenteric plexus in the form of a thin row of cells encircling the inception of the ganglia. These cells were multipolar or spindle-shaped with two long processes and corresponded to the ICC of the myenteric plexus. In the proximal colon, c-kit-IR cells emerged at week 9-10 in the form of two parallel belts of cells extending at the submucosal plexus and the myenteric plexus levels. We conclude that ICC develop following two different patterns in the human midgut.
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Affiliation(s)
- Mirjana Abramovic
- Institute of Chemistry, Faculty of Medicine, University of Nis, 81 Dr Zorana Djindjica Blvd, 18000, Nis, Serbia
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13
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Abstract
Hirschsprung disease (HD) is the most prevalent congenital gastrointestinal motility disorder. The pathogenesis of HD is defined as a functional intestinal obstruction resulting from a defect in the intrinsic innervation of the distal bowel. In addition to the enteric nervous system, the interstitial cells of Cajal (ICC) play an important role in the generation of coordinated gastrointestinal peristalsis. The major function of the ICCs is the generation of slow waves that allow these cells to act as specialised pacemaker cells within various tissues. ICCs have additional functions in the gastrointestinal tract as regulators of mechanical activity and neurotransmission. Due to the central role of ICCs in gastrointestinal peristalsis, it has been suggested that defects or impairments of the ICCs may contribute to motility dysfunction in several gastrointestinal motility disorders. This review describes the distribution and functions of ICCs in the normal gut and in Hirschsprung disease.
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Affiliation(s)
- Stefan Gfroerer
- Department of Paediatric Surgery, University Hospital, Goethe University Frankfurt/M, 60596 Frankfurt/M, Germany,
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14
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Radenkovic G. Two patterns of development of interstitial cells of Cajal in the human duodenum. J Cell Mol Med 2012; 16:185-92. [PMID: 21352475 PMCID: PMC3823104 DOI: 10.1111/j.1582-4934.2011.01287.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
At the end of the embryonic period of human development, c-kit immunoreactive (c-kit IR) cells identifiable as interstitial cells of Cajal (ICC) are present in the oesophagus and stomach wall. In the small and large bowel, c-kit-IR cells appear later (in the small bowel at 9 weeks, and in the colon at 10-12 weeks), also in the MP region. The object of this study was to determine the timing of appearance and distribution of c-kit IR cells in the human embryonic and foetal duodenum. I used immunohistochemistry to examine the embryonic and foetal duodenum for cells expressing CD117 (Kit), expressed by mature ICC and ICC progenitor cells and CD34 to identify presumed ICC progenitors. Enteric plexuses were examined by way of antineuron-specific enolase and the differentiation of smooth muscle cells was studied using antidesmin antibodies. At the end of the embryonic period of development, c-kit IR cells were solely present in the proximal duodenum in the form of a wide belt of densely packed cells around the inception of the myenteric plexus (MP) ganglia. In the distal duodenum, c-kit IR cells emerged at the beginning of the foetal period in the form of thin rows of pleomorphic cells at the level of the MP. From the beginning of the fourth month, the differences in the distribution of ICC in the different portions of the duodenum were established, and this relationship was still present in later developmental stages. In fact, in the proximal duodenum, ICC of the MP (ICC-MP), ICC of the circular muscle (ICC-CM) and ICC of the septa (ICC-SEP) were present, and in the distal duodenum ICC-MP and ICC-SEP only. In conclusion, in the humans there is a difference in the timing and patterns of development of ICC in the proximal duodenum compared to the distal duodenum.
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Affiliation(s)
- Goran Radenkovic
- Department of Histology and Embryology, University of Nis, Nis, Serbia.
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Radenkovic G, Abramovic M. Differentiation of interstitial cells of Cajal in the human distal colon. Cells Tissues Organs 2012; 196:463-9. [PMID: 22652525 DOI: 10.1159/000336707] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/18/2012] [Indexed: 01/06/2023] Open
Abstract
At the end of the embryonic period of human development, interstitial cells of Cajal (ICC) are present in the esophagus, stomach, and proximal duodenum, around the inception of the myenteric plexus (MP) ganglia. In the small and large bowel, ICC appear later. The object of the present study was to determine the timing of appearance and pattern of distribution of ICC in the human embryonic and fetal distal colon. Human distal colon specimens were obtained from 8 embryos and 14 fetuses without gastrointestinal disorders. The specimens were 7-16 weeks of gestational age. The specimens were exposed to anti-c-kit antibodies to investigate ICC differentiation. Enteric plexuses were immunohistochemically examined using anti-neuron-specific enolase, and the differentiation of smooth muscle cells was studied with anti-desmin antibodies. In the distal colon, ICC emerged at weeks 10-11 of the fetal period in the form of two parallel belts of densely packed cells extending at the submucous plexus (SMP) and the MP level. These cells correspond to ICC of the SMP (ICC-SMP) and ICC of the MP (ICC-MP). The simultaneous appearance of ICC at the SMP and MP level in the distal colon can be explained by the fact that there are differences in the migration of neural crest cells in particular portions of the digestive tube. In conclusion, in humans, there was a difference in the patterns of development of ICC in the distal colon compared to the rest of the gut.
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Affiliation(s)
- Goran Radenkovic
- Department of Histology and Embryology, Faculty of Medicine, University of Nis, Nis, Serbia.
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16
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An immunohistochemical study of S-100 protein in the intestinal tract of Chinese soft-shelled turtle, Pelodiscus sinensis. Res Vet Sci 2011; 91:e16-24. [DOI: 10.1016/j.rvsc.2011.02.015] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2008] [Revised: 01/28/2011] [Accepted: 02/18/2011] [Indexed: 01/17/2023]
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17
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Radenkovic G, Savic V, Mitic D, Grahovac S, Bjelakovic M, Krstic M. Development of c-kit immunopositive interstitial cells of Cajal in the human stomach. J Cell Mol Med 2010; 14:1125-34. [PMID: 19298525 PMCID: PMC3822749 DOI: 10.1111/j.1582-4934.2009.00725.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Interstitial cells of Cajal (ICC) include several types of specialized cells within the musculature of the gastrointestinal tract (GIT). Some types of ICC act as pacemakers in the GIT musculature, whereas others are implicated in the modulation of enteric neurotransmission. Kit immunohistochemistry reliably identifies the location of these cells and provides information on changes in ICC distribution and density. Human stomach specimens were obtained from 7 embryos and 28 foetuses without gastrointestinal disorders. The specimens were 7-27 weeks of gestational age, and both sexes are represented in the sample. The specimens were exposed to anti-c-kit antibodies to investigate ICC differentiation. Enteric plexuses were immunohistochemically examined by using anti-neuron specific enolase and the differentiation of smooth muscle cells (SMC) was studied with anti-alpha smooth muscle actin and anti-desmin antibodies. By week 7, c-kit-immunopositive precursors formed a layer in the outer stomach wall around myenteric plexus elements. Between 9 and 11 weeks some of these precursors differentiated into ICC. ICC at the myenteric plexus level differentiated first, followed by those within the muscle layer: between SMC, at the circular and longitudinal layers, and within connective tissue septa enveloping muscle bundles. In the fourth month, all subtypes of c-kit-immunoreactivity ICC which are necessary for the generation of slow waves and their transfer to SMC have been developed. These results may help elucidate the origin of ICC and the aetiology and pathogenesis of stomach motility disorders in neonates and young children that are associated with absence or decreased number of these cells.
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Affiliation(s)
- Goran Radenkovic
- Department of Histology and Embryology, Faculty of Medicine, University of Nis, Nis, Serbia.
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18
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Wittmeyer V, Merrot T, Mazet B. Tonic inhibition of human small intestinal motility by nitric oxide in children but not in adults. Neurogastroenterol Motil 2010; 22:1078-e282. [PMID: 20546504 DOI: 10.1111/j.1365-2982.2010.01532.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Gastrointestinal motility is dependent on neural influences that largely involve the enteric nervous system (ENS). The main motor patterns that occur in the fasted and fed state are noticeably different in children compared with adults. Although the development of the ENS continues after birth, there is no data on the contractile activity of segments of small intestine from young children. This study was designed to provide data on the development of muscle control by the human ENS with particular attention to acetylcholine (ACh) and nitric oxide (NO) as the primary neurotransmitters of enteric motor neurons, respectively. METHODS Small intestinal specimens were obtained from 11 children and six adults undergoing surgery for various diseases. The mechanical activity of the circular muscle was recorded in vitro. The effects of N(ω)-nitro-L-arginine methyl ester hydrochloride, an inhibitor of NO synthesis, and of atropine, an antagonist of muscarinic receptors, were tested on the spontaneous motility and responses to nerve stimulation. KEY RESULTS Spontaneous motility was observed in all preparations. Responses to nerve stimulation were identical in child and adult. No tonic cholinergic excitation of small intestinal motility was observed either in child or in adult. Inhibition of NO synthesis induced a major disinhibition of motility in child but not in adult. CONCLUSIONS & INFERENCES Spontaneous intestinal motility and cholinergic and nitrergic neurotransmission are present from birth. NO provides a tonic inhibition of intestinal motility only in child. Our study indicates that NO may be a major player in shaping the ontogenic development of intestinal motility in human.
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Affiliation(s)
- V Wittmeyer
- Département de Chirurgie et Orthopédie de l'Enfant, Hôpital Jeanne de Flandre, CHRU de Lille, Lille cedex, France
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Fintl C, Hudson NPH. The interstitial cells of Cajal of the equine gastrointestinal tract: what we know so far. Equine Vet J 2010; 42:372-7. [PMID: 20525058 DOI: 10.1111/j.2042-3306.2010.00073.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Gastrointestinal motility disorders are a serious problem in both veterinary and human medicine and may represent a dysfunction of the neural, muscular or pacemaker components (interstitial cells of Cajal) of bowel control. The interstitial cells of Cajal are considered to be the pacemakers and mediators of certain forms of neurotransmission in the gastrointestinal tract. These cells have been implicated, either primarily or secondarily, in the pathogenesis of gastrointestinal disease processes in which there is a prominent element of disturbance to intestinal motility. In the horse, their involvement has been implicated in large intestinal obstructive colic and grass sickness (equine dysautonomia). This review highlights the properties of the interstitial cells of Cajal and the role these cells play in orchestrating gastrointestinal motility patterns. In addition, it examines their role in intestinal motility disorders and summarises our current understanding of their importance in the equine gastrointestinal tract.
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Affiliation(s)
- C Fintl
- Norwegian School of Veterinary Science, Department of Companion Animal Clinical Sciences, PO Box 8146 Dep., 0033 Oslo, Norway
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20
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Disorders of interstitial cells of Cajal in a neonate with segmental dilatation of the intestine. J Pediatr Surg 2010; 45:e11-4. [PMID: 20620293 DOI: 10.1016/j.jpedsurg.2010.03.024] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2009] [Revised: 03/21/2010] [Accepted: 03/22/2010] [Indexed: 11/23/2022]
Abstract
Localized myopathy of the muscular layers may be an important factor contributing to segmental dilatation of the intestine (SDI). Only one report has described SDI of the jejunum in a neonate showing no abnormality of the interstitial cells of Cajal (ICC). The present report describes the very rare case of a neonatal girl with segmental dilatation of the distal duodenum and proximal jejunum with irregular arrangements of Auerbach's plexus and ICC and the successful surgical treatment of SDI. We review the literature on this type of relationship between abnormality of ICC and SDI and discuss the clinical features of this complication. Furthermore, the possible neuropathic cause of SDI complicated with disorders of ICC was explored in this report.
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C-kit-immunopositive interstitial cells of Cajal in human embryonal and fetal oesophagus. Cell Tissue Res 2010; 340:427-36. [PMID: 20431920 DOI: 10.1007/s00441-010-0957-9] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2010] [Accepted: 02/25/2010] [Indexed: 01/28/2023]
Abstract
Interstitial cells of Cajal (ICC) are morphologically and functionally intercalated between the elements of the enteric nervous system and the smooth muscle cells (SMCs) in the musculature of the digestive tract. Kit immunohistochemistry reliably identifies the location of these cells and provides information on changes in ICC distribution and density. Human oesophagus specimens (7 embryos, 23 fetuses at 7-27 weeks gestational age; both sexes) were exposed to Kit antibodies to determine ICC differentiation. Enteric plexuses were examined immunohistochemically by using anti-neuron-specific enolase, whereas the differentiation of SMCs was studied with antibodies against alpha-smooth-muscle actin and desmin. By week 7, c-kit-immunopositive cells were present along the entire oesophagus in the form of an uninterrupted layer around the myenteric plexus (MP) elements. From the beginning of the 3rd month, the number of ICC progressively decreased around the MP ganglia but increased within the muscle layers. Concomitantly, differences in the number and distribution of ICC were established in the various portions of the oesophagus: specifically, ICC were abundant in the lower portion, less numerous in the middle region and rare in the upper part. By the 5th month of development, the relationship as found in later developmental stages had been established: C-kit IR ICC were present within the circular muscle layer, within the longitudinal layer and in the connective septa surrounding the muscle bundles but were completely missing around the MP ganglia.
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22
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Tander B, Bicakci U, Sullu Y, Rizalar R, Ariturk E, Bernay F, Kandemir B. Alterations of Cajal cells in patients with small bowel atresia. J Pediatr Surg 2010; 45:724-8. [PMID: 20385278 DOI: 10.1016/j.jpedsurg.2009.11.010] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2009] [Revised: 11/16/2009] [Accepted: 11/16/2009] [Indexed: 01/15/2023]
Abstract
PURPOSE Interstitial cells of Cajal (ICC) are regarded as the pacemaker cells of the gastrointestinal tract. There are some well-designed studies investigating the structure and function of ICC subsequent to experimentally induced intestinal obstructions. However, it remains unclear whether reduction of number of ICC primarily leads to mechanical obstruction of the bowel such as seen in intestinal atresia. We aimed to investigate the number of ICC in proximal and distal parts of the atresias of patients with small bowel atresia. PATIENTS AND METHODS Twenty-one patients (13 male and 8 female; median age, 3 days; median gestation age, 38 weeks) with jejunal or ileal atresia underwent primary repair between 2001 and 2009. The demographic data were reviewed. The specimen of the distal and proximal parts of the atretic segments was investigated according to presence and number of ICC in the myenteric plexus using immunohistochemical methods. The jejunum segments of 14 newborns who died from causes other than bowel disease were examined as a control. Scoring and count systems were developed for the evaluation of ICC. A continuous layer of CD-117 immunoreactive Cajal cells around the myenteric plexus was scored as 3, whereas discontinuous and diminished Cajal cells were scored as 2. Few and sparse Cajal cells around the myenteric ganglia and in the muscle layer were scored as 1. If there was no Cajal cell at all, it was scored as zero. In addition, the number of ICC per field was counted. The scores and the numbers of ICC per field were compared in patients with small bowel atresia and control group. RESULTS All patients but one survived. One patient was lost because of congenital cardiac anomalies. The median score of control subjects was 3 (range, 1-3). Both the proximal and distal segments of the atretic bowel had a median score of 1 in patients with atresia. Twenty patients' score of proximal (95%) and 19 patients' score of distal bowel segment (90%) had an ICC score of 2 or less. Only 1 control subject (7%) had an ICC score of less than 2. Results were statistically significant in controls and patients. The mean number of ICC in the control group was 5.36 +/- 2.36; in distal segments of patients with atresia, it was 1.03 +/- 1.4; and in proximal segments, it was 0.82 +/- 1.56. The difference between the control group and the patients was statistically significant (P < .05). CONCLUSION We demonstrated a remarkable decrease of ICC in small bowel wall of patients with intestinal atresia; but we could not show whether the reduction of ICC is a primary event, which also participates in the pathogenesis of intestinal atresia, or whether the mechanical obstruction caused by any unknown etiology (eg, ischemia) leads to decrease in number of ICC.
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Affiliation(s)
- Burak Tander
- Department of Pediatric Surgery, Ondokuz Mayis University, Kurupelit, 55139 Samsun, Turkey.
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Midrio P, Vannucchi MG, Pieri L, Alaggio R, Faussone-Pellegrini MS. Delayed development of interstitial cells of Cajal in the ileum of a human case of gastroschisis. J Cell Mol Med 2008; 12:471-8. [PMID: 18266958 PMCID: PMC3822536 DOI: 10.1111/j.1582-4934.2008.00277.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2008] [Accepted: 02/05/2008] [Indexed: 12/12/2022] Open
Abstract
The Interstitial Cells of Cajal (ICC) are responsible for rhythmic electrical activity. A paralytic ileus is present in gastroschisis (GS), a malformation due to a defective closure of the abdominal wall through which part of the intestine herniates during pregnancy. In experimental GS, ICC morphological immaturity was shown in the rat foetus at-term but it could not be demonstrated whether differentiation is accomplished post-natally. For this purpose we morphologically investigated ICC, as well as enteric neurons and smooth muscle cells, in a case of human GS at birth and 1 month later when peristaltic activity had initiated. A 36 weeks gestation female was born by c/section with prenatal diagnosis of GS and possible volvulus of the herniated intestine. At birth, the necrotic intestine was resected and both ileostomy and colostomy were performed. The intestine continuity was restored after 4 weeks. Intestinal specimens, taken during both operations at the level of the proximal stoma, were immunostained with c-kit, neuron-specific-enolase and alpha-smooth-muscle-actin antibodies and some processed for electron microscopy. ICC were present at the myenteric plexus only. At birth, these cells were rare and ultrastructurally immature; 1 month later, when partial enteral feeding was tolerated, they formed rows or groups and many of them were ultrastructurally differentiated. Neurons and smooth muscle cells, immature at birth, had developed after 1 month. Therefore, ICC differentiation, as well as that of neurons and smooth muscle cells, is delayed at birth and this might explain the paralytic ileus in GS. One month later, differentiation quickly proceeded at all cellular levels paralleling the increasing tolerance of enteral nutrition.
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Affiliation(s)
- Paola Midrio
- Department of Pediatric Surgery, University of Padua, Padua, Italy
| | | | - Laura Pieri
- Department of Anatomy, Histology and Forensic Medicine, University of Florence, Florence, Italy
| | - Rita Alaggio
- Department of Pathology, University of Padua, Padua, Italy
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Rolle U, Piaseczna-Piotrowska A, Puri P. Interstitial cells of Cajal in the normal gut and in intestinal motility disorders of childhood. Pediatr Surg Int 2007; 23:1139-1152. [PMID: 17968564 DOI: 10.1007/s00383-007-2022-7] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Interstitial cells of Cajal (ICCs) are pacemaker cells which are densely distributed throughout the whole gastrointestinal tract. ICCs have important functions in neurotransmission, generation of slow waves and regulation of mechanical activities in the gastrointestinal tract, especially for the coordinated gastrointestinal peristalsis. Therefore, a loss of ICCs could result in gastrointestinal motor dysfunction. In recent years c-kit labeling has been widely used to study pathological changes of ICCs in gastrointestinal motility disorders. Paediatric gastrointestinal motility disorders such as hypertrophic pyloric stenosis, Hirschsprung's disease, total colonic aganglionosis, hypoganglionosis, intestinal neuronal dysplasia, internal anal sphincter achalasia, megacystis microcolon intestinal hypoperistalsis syndrome have been reported to be associated with loss or deficiency of ICCs networks. This review describes the distribution of ICCs in the normal gastrointestinal tract and its altered distribution in intestinal motility disorders of childhood.
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Affiliation(s)
- Udo Rolle
- Department of Paediatric Surgery, University of Leipzig, Leipzig, Germany
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25
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Faussone-Pellegrini MS, Vannucchi MG, Alaggio R, Strojna A, Midrio P. Morphology of the interstitial cells of Cajal of the human ileum from foetal to neonatal life. J Cell Mol Med 2007; 11:482-94. [PMID: 17635640 PMCID: PMC3922354 DOI: 10.1111/j.1582-4934.2007.00043.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2007] [Accepted: 04/17/2007] [Indexed: 11/30/2022] Open
Abstract
The so-called interstitial cells of Cajal myenteric plexus (ICC-MP), interstitial cells of Cajal intramuscular (ICC-IM) and interstitial cells of Cajal deep muscular plexus (ICC-DMP) are the three types of ICC endowed within the intestinal muscle coat where they play different roles in gut motility. Studies on ICC ontogenesis showed ICC-MP in the human ileum by 7-9 weeks while information on ICC-IM and ICC-DMP in foetuses and newborns are not exhaustive. Functional recordings in the fasting state of prematurely born babies aged 28-37 weeks showed immature ileal motility. To gain more information on the time of appearance of the three ICC types in the human ileum and on the steps of the acquisition of mature features, we studied by c-kit immuno-histochemistry foetuses aged 17-27 weeks and newborns aged 36-41 weeks. In parallel, the maturative steps of enteric plexuses and muscle layers were immunohistochemically examined by using anti-neuron specific enolase (NSE), anti-S-100 and anti-alpha smooth muscle actin (alphaSMA) antibodies. The appearance and differentiation of all the ICC types were seen to occur in concomitance with those of the related nerve plexuses and muscle layers. ICC-MP appeared first, ICC-IM and ICC-DMP later and their differentiation was incomplete at birth. In conclusion, the ICC-MP, the intestinal pacemaker cells, in spite of absence of food intake, are already present during the foetal life and the ICC-IM appear by pre-term life, thus ensuring neurotransmission. The ICC-DMP and their related nerve plexus and smooth muscle cells, i.e. the intestinal stretch receptor, begin to differentiate at birth. These findings might help in predicting neonatal ileal motor behaviour and in interpreting the role of ICC abnormalities in the pathophysiology of intestinal motile disorders of neonates and young children.
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Holmberg A, Olsson C, Hennig GW. TTX-sensitive and TTX-insensitive control of spontaneous gut motility in the developing zebrafish (Danio rerio) larvae. J Exp Biol 2007; 210:1084-91. [PMID: 17337720 DOI: 10.1242/jeb.000935] [Citation(s) in RCA: 69] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
SUMMARY
Spontaneous regular gut motility in zebrafish begins around 4 days post fertilisation (d.p.f.) and is modulated by release of acetylcholine and nitric oxide. The role of intrinsic or extrinsic innervation for initiating and propagating the spontaneous contractions, however, is not well understood. By creating spatiotemporal maps, we could examine spontaneous motility patterns in zebrafish larvae in vivo at 4 and 7 d.p.f. in more detail. Tetrodotoxin (TTX) was added to elucidate the importance of nervous control. Anterograde and retrograde contraction waves originated in the same region,just posterior to the intestinal bulb. This area correlates well with the distribution of Hu (human neuronal protein C/D)-immunoreactive nerve cell bodies. Whereas numerous immunoreactive nerve cells were present in the mid and distal intestine at both 4 and 7 d.p.f., fewer cells were seen anterior to the origin of contractions. The overall frequency of contractions(1.16±0.15 cycles min–1, N=14 at 4 d.p.f.;1.05±0.09 cycles min–1, N=13 at 7 d.p.f.) and the interval between individual anterograde contraction waves (54.8±7.9 s at 4 d.p.f., N=14; 56.9±4.4 s, N=13 at 7 d.p.f.)did not differ between the two stages but the properties of the contractions were altered. The distance travelled by each wave increased from 591.0±43.8 μm at 4 d.p.f. (N=14) to 719.9±33.2 μm at 7 d.p.f. (N=13). By contrast, the velocity decreased from 4 d.p.f.(49.5±5.5 μm s–1, N=12) to 7 d.p.f.(27.8±3.6 μm s–1, N=13). At 4 d.p.f., TTX did not affect any of the parameters whereas at 7 d.p.f. anterograde frequency(control 1.07±0.12 cycles min–1, N=8; TTX 0.55±0.13 cycles min–1, N=8) and distance travelled (control 685.1±45.9 μm, N=8; TTX 318.7±88.7 μm, N=6) were decreased. In conclusion, enteric or extrinsic innervation does not seem to be necessary to initiate spontaneous contractions of the gut in zebrafish larvae. However, later in development,nerves have an increasingly important role as modulators of intestinal activity.)
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Affiliation(s)
- Anna Holmberg
- Department of Zoophysiology, Göteborg University, SE 405 30 Göteborg, Sweden
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27
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Nathan DG. The cancer treatment revolution. TRANSACTIONS OF THE AMERICAN CLINICAL AND CLIMATOLOGICAL ASSOCIATION 2007; 118:317-323. [PMID: 18528513 PMCID: PMC1863594] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 05/26/2023]
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Mei F, Yu B, Ma H, Zhang HJ, Zhou DS. Interstitial cells of Cajal could regenerate and restore their normal distribution after disrupted by intestinal transection and anastomosis in the adult guinea pigs. Virchows Arch 2006; 449:348-57. [PMID: 16912883 DOI: 10.1007/s00428-006-0258-6] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2006] [Accepted: 06/16/2006] [Indexed: 10/24/2022]
Abstract
Surgical manipulations of the gastrointestinal (GI) tract usually lead to loss of interstitial cells of Cajal (ICCs). The present study prepared to investigate whether ICCs can regenerate and restore their normal distribution up to 5 months after semitransection and end-to-end anastomosis of small intestines of adult guinea pigs. The segments of anastomosis were studied by immunohistochemistry with anti-KIT, 5-bromo-2'-deoxyuridine (BrdU), stem cell factor (SCF), and neurofilament 200 antibodies and also by transmission electron microscopy (TEM). At early stage, intestinal surgery led to intestinal wall impairment and ICCs loss, and ICCs near the site of anastomosis gradually increased in numbers. About 150 days postoperation, the distribution of ICCs and the microstructure of intestinal wall appeared to be similar with those of the control. By double immunostaining with BrdU and KIT antibodies, a number of proliferated ICCs were seen near the site of transection/anastomosis. Furthermore, KIT ligand, SCF, was mainly observed in the smooth muscle cells (SMCs), which are located close to ICCs. TEM observation revealed a number of immature and mature ICCs in this region. Our results indicated that ICCs could regenerate and restore their normal distribution after intestinal surgery and SMCs might be involved in the regenerated events of ICCs in the adult guinea pig GI tract.
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Affiliation(s)
- Feng Mei
- Department of Histology and Embryology, Third Military Medical University, Chongqing, 400038, People's Republic of China
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Shafik A, Shafik AA, El-Sibai O, Shafik IA. Interstitial cells of cajal in patients with constipation due to total colonic inertia. J INVEST SURG 2006; 19:147-53. [PMID: 16809224 DOI: 10.1080/08941930600674637] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Colonic wall contains interstitial cells of Cajal. In view of studies demonstrating that Cajal cells generate electric waves which are presumably responsible for colonic motor activity, and that these waves are absent in total colonic inertia, we investigated the hypothesis that colonic Cajal cells might be disordered in patients with total colonic inertia. The study comprised 28 patients (age 41.6 +/- 8.2 SD years, 19 women, 9 men) with total colonic inertia in whom total colectomy was performed. Colonic specimens obtained from normal segments of the excised colon of 24 cancer patients acted as controls. Specimens were subjected to c-kit immunohistochemistry. Controls for antisera specificity consisted of tissue incubated with normal rabbit serum that had been substituted for the primary antiserum. C-kit-positive branched Cajal-like cells were detected in the musculature of the normal colonic segments. They were distinguishable from the C-kit-negative smooth muscle cells and the C-kit-positive but unbranched mast cells. No Cajal cells were detected in colon of total colonic inertia patients. The absence of Cajal cells in patients with total colonic inertia can be assumed to explain the absence of electric waves and motile activity previously reported in these patients. Further studies are needed to investigate the cause of Cajal-cell absence.
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Affiliation(s)
- Ahmed Shafik
- Department of Surgery and Experimental Research, Faculty of Medicine, Cairo University, Cairo, Egypt.
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Shafik A, El Sibai O, Ahmed I. The identification of specialized pacemaking cells in the anal sphincters. Int J Colorectal Dis 2006; 21:453-7. [PMID: 16088385 DOI: 10.1007/s00384-005-0026-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/27/2005] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIMS Interstitial cells of Cajal (ICC) are claimed to generate the electrical activity in the colon and stomach. As the external (EAS) and internal (IAS) anal sphincters exhibit resting electrical activity, we hypothesized the presence of ICC in these sphincters. This hypothesis was investigated in the current study. PATIENTS/METHODS Specimens from the EAS and IAS were taken from normal areas of the anorectum which had been surgically excised by abdominoperineal operation for rectal cancer of 28 patients (16 men, 12 women, mean age 42.2+/-4.8 years). The specimens were subjected to c-kit immunohistochemistry. Controls for the specificity of the antisera consisted of tissue incubation with normal rabbit serum substituted for the primary antiserum. RESULTS/FINDINGS Fusiform, c-kit positive, ICC-like cells were detected in the anal sphincters; they had dendritic processes. They were clearly distinguishable from the non-branching, c-kit negative smooth and striated muscle cells of the anal sphincters. The specimens contained also c-kit positive mast cells, but they had a rounded body with no dendritic processes. Immunoreactivity was absent in negative controls in which the primary antibody was omitted. INTERPRETATION/CONCLUSION We have identified, for the first time, cells in EAS and IAS with morphological and immunological phenotypes similar to ICCs of the gut. These cells appear to be responsible for initiating the slow waves recorded from the anal sphincters and for controlling their activity. A deficiency or absence of these cells may affect the anal motile activity. Studies are needed to explore the role of these cells in anal motility disorders.
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Affiliation(s)
- Ahmed Shafik
- Department of Surgery and Experimental Research, Faculty of Medicine, Cairo University, Cairo, Egypt.
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Shafik A, Shafik I, El Sibai O, Shafik AA. Electric waves recorded from the testicle: are they capsular or from the testicular tissue? ACTA ACUST UNITED AC 2005; 28:350-4. [PMID: 16300667 DOI: 10.1111/j.1365-2605.2005.00564.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
We demonstrated in a previous study that electric waves could be recorded from the testicle by applying the electrodes either directly to the tunica albuginea (TA) or transcutaneously. As the TA contains smooth muscle fibres which presumably transmit the electric waves, we investigated the hypothesis that the electric waves recorded from the testicle originated from the TA. During the repair of inguino-scrotal hernia in 24 men [age 36.6 +/- 8.6 years (mean +/- SD)], the tunica vaginalis was everted because of the presence of hydrocele. The electric activity of the TA was recorded by three surface electrodes and that of the testicle by three needle electrodes. The recorded potentials were amplified and displayed on an electromyographic apparatus. Triphasic slow waves (SWs) were recorded from the TA. They showed similar frequency, amplitude and conduction velocity from the three electrodes of the individual subject and were reproducible. They were followed or superimposed by bursts of action potentials (APs) which occurred randomly. No waves were recorded from the three needle electrodes inserted into the testicular tissue. The current study could demonstrate that the electric waves recorded from the electrodes applied to the testicle were derived from the TA and not from the testicular tissue. This finding apparently denotes that the TA has a resting tone and probably motile activity, the role of which in testicular function needs to be studied.
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Affiliation(s)
- Ahmed Shafik
- Department of Surgery and Experimental Research, Faculty of Medicine, Cairo University, Cairo, Egypt
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Shafik A, Shafik I, el-Sibai O. Identification of c-kit-positive cells in the human prostate: the interstitial cells of Cajal. ACTA ACUST UNITED AC 2005; 51:345-51. [PMID: 16087562 DOI: 10.1080/014850190944456] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
The prostate exhibits electric activity in the form of slow waves (SWs) and action potentials (APs). As the interstitial cells of Cajal (ICCs) are considered the pacemaker cells which generate the electric waves, we investigated the hypothesis that the prostate contains ICC. Prostatic biopsies were obtained from 15 healthy volunteers (mean age 36 +/- 3.8 SD years). They were subjected to c-kit immunohistochemistry. Controls for the specificity of the antisera consisted of tissue incubated with normal rabbit serum substituted for the primary antiserum. C-kit-positive cells were identified as fusiform with dendritic processes. The cytoplasm was granular and the nucleus large and oval. Mast cells, also c-kit-positive, were round and lacked the dendritic processes. Immunoreactivity was absent in the negative controls. There were cells in the prostate with morphological and immunological phenotypes similar to ICCs of the gut. We predict an abnormal distribution of these cells in prostatic diseases. The study of the integrity of these cells may prove to be a useful investigative tool in the diagnosis of prostatic diseases and in the planning of an appropriate treatment.
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Affiliation(s)
- A Shafik
- Department of Surgery and Experimental Research, Faculty of Medicine, Cairo University, Cairo, Egypt.
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Abstract
AIM: In order to investigate the pacing mechanism of the interstitial cells of Cajal (ICC), the method for isolation and culture of ICC from the Wistar rat stomach was explored.
METHODS: The gastric tissue of Wistar rat was dissected. Collagenase was used to isolate ICC. The cells were suspended in smooth muscle cell medium containing stem cell factor. The medium was changed every other day until the cells were used. The c-Kit antibody was applied to label ICC to distinguish them from smooth muscle cells.
RESULTS: ICC in culture maintained the intrinsic characteristics: multiple processes, large nuclei, and intercellular network. Fluorescent staining with c-Kit antibody confirmed that the culture ICC was successful.
CONCLUSION: ICC has been isolated by enzyme digestion method from Wistar rat stomach and cultured successfully.
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Wallace AS, Burns AJ. Development of the enteric nervous system, smooth muscle and interstitial cells of Cajal in the human gastrointestinal tract. Cell Tissue Res 2005; 319:367-82. [PMID: 15672264 DOI: 10.1007/s00441-004-1023-2] [Citation(s) in RCA: 160] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2004] [Accepted: 10/19/2004] [Indexed: 12/16/2022]
Abstract
The generation of functional neuromuscular activity within the pre-natal gastrointestinal tract requires the coordinated development of enteric neurons and glial cells, concentric layers of smooth muscle and interstitial cells of Cajal (ICC). We investigated the genesis of these different cell types in human embryonic and fetal gut material ranging from weeks 4-14. Neural crest cells (NCC), labelled with antibodies against the neurotrophin receptor p75NTR, entered the foregut at week 4, and migrated rostrocaudally to reach the terminal hindgut by week 7. Initially, these cells were loosely distributed throughout the gut mesenchyme but later coalesced to form ganglia along a rostrocaudal gradient of maturation; the myenteric plexus developed primarily in the foregut, then in the midgut, and finally in the hindgut. The submucosal plexus formed approximately 2-3 weeks after the myenteric plexus, arising from cells that migrated centripetally through the circular muscle layer from the myenteric region. Smooth muscle differentiation, as evidenced by the expression of alpha-smooth muscle actin, followed NCC colonization of the gut within a few weeks. Gut smooth muscle also matured in a rostrocaudal direction, with a large band of alpha-smooth muscle actin being present in the oesophagus at week 8 and in the hindgut by week 11. Circular muscle developed prior to longitudinal muscle in the intestine and colon. ICC emerged from the developing gut mesenchyme at week 9 to surround and closely appose the myenteric ganglia by week 11. By week 14, the intestine was invested with neural cells, longitudinal, circular and muscularis mucosae muscle layers, and an ICC network, giving the fetal gut a mature appearance.
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Affiliation(s)
- Adam S Wallace
- Neural Development Unit, Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, UK
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Khen N, Jaubert F, Sauvat F, Fourcade L, Jan D, Martinovic J, Vekemans M, Landais P, Brousse N, Leborgne M, Nihoul-Fékété C, Cerf-Bensussan N, Sarnacki S. Fetal intestinal obstruction induces alteration of enteric nervous system development in human intestinal atresia. Pediatr Res 2004; 56:975-80. [PMID: 15496609 DOI: 10.1203/01.pdr.0000145294.11800.71] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Intestinal motility disorders are a major cause of morbidity after surgical repair of intestinal atresia of unknown mechanism. We hypothesized that interruption of antenatal peristalsis may disturb the normal development of the enteric nervous system. Using a series of neuronal (synaptophysin, neuronal nitric oxide synthase, neurofilaments) and nonneuronal markers (glial acidic fibrillary protein and c-Kit) and immunohistochemistry, we have defined developmental steps of the enteric nervous system in normal intestine (12 fetuses, 15 children, and 4 adults) and their alterations above and below the obstacle in 22 human intestinal atresia compared with age-matched controls. Antisynaptophysin antibody revealed the progressive conversion of the myenteric plexus from a continuous belt into regularly spaced ganglions during normal fetal gut development and, by contrast, the significantly delayed appearance of individual neuronal ganglions in the distal segments of atresia (p < 0.05). Staging using three other markers for neuronal (neurofilaments and neuronal nitric oxide synthase) and nonneuronal cells (glial acidic fibrillary protein) confirmed that maturation of the myenteric plexus was significantly delayed below atresia (p < 0.01). These results indicate that intestinal atresia impairs the development of the enteric nervous system and provide an anatomical substrate for the motility disorders observed after surgical repair. They point to the role of peristalsis in normal gut development and suggest that stimulation of peristalsis might be used to accelerate recovery.
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Affiliation(s)
- Naziha Khen
- INSERM E-0212, Faculty Necker, 75743 Paris Cedex 15, France
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Lin L, Xu HC, Zhang HJ, Hu YD, Lin Z, Zhao ZQ. Alterations of Cajal cell in colon of slow transit constipation mice. Shijie Huaren Xiaohua Zazhi 2004; 12:2107-2110. [DOI: 10.11569/wcjd.v12.i9.2107] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To establish an animal model of slow transit constipation and to investigate the relationship between interstitial cell of Cajal in colon and the pathophysiological changes in the model of slow transit constipation.
METHODS: The mouse model was established by subcutaneous injection of morphine. According to period of morphine injected, the mice were divided into two groups: 2.5 mg/kg/per day ×30 d (n = 15) and 2.5 mg/kg/per day ×45 d (n = 15), and corresponding control groups were established by injecting the same dosage of 9 g/L sodium chloride solution. Fecal weight was recorded daily, and transit function of intestine was measured by activated charcoal suspension pushing test. The changes of interstitial cell of Cajal were observed by immunohistochemistry.
RESULTS: Fecal weight daily in test groupⅠwas less than control groupⅠ(18.8±3.2 g vs 20.6±1.8 g, P <0.05), and test groupⅡwas less than control group Ⅱ (16.8±2.0 g vs 22.0±3.2 g, P <0.01). It showed the significance of difference between the test groupⅠvs test groupⅡ(P <0.05), and no difference between two control groups (P >0.05). Intestinal transit rate in test group Ⅰwas lower than control groupⅠ(45.3±1.5% vs 49.2±1.8%, P <0.05), and test group Ⅱwas lower than control groupⅡ(40.6±1.3% vs 50.6±3.0%, P <0.01). There was a significant difference between test groupⅠvs test groupⅡ(P <0.05), and no difference between two control groups (P >0.05). Colon tissue c-kit+ cell's area in test groupⅠwas more decreased than that of control groupⅠ(81.3±7.9 ten thousand mm2vs 98.6±8.0 ten thousand mm2, P <0.01), and test group Ⅱvs control groupⅡwas 66.5±8.4 vs 100.9±10.0 ten thousand mm2 (P <0.01). There was a significant difference between the testⅠand testⅡ(P <0.01),and no difference in two control groups (P >0.05).
CONCLUSION: Daily fecal mass, intestinal transit ratio and the number of interstitial cells of Cajal are decreased in the mouse model of slow intestinal transit movement induced by morphine and have a positive correlation with period of morphine injected.
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Shafik A, Shafik I, el-Sibai O, Shafik A, Mostafa RM. Vesical pacing in patients with overactive bladder: technique and results. Int Urol Nephrol 2004; 36:29-34. [PMID: 15338669 DOI: 10.1023/b:urol.0000032674.57294.16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
OBJECTIVES A recent study has demonstrated that the electric activity of the overactive bladder (OAB) is 'dysrhythmic'. The cause was attributed to a disordered vesical pacemaker which discharges these waves. In a subsequent study, the dysrhythmic waves have been 'normalized' by vesical pacing and the optimal parameters which are required to achieve normalization have been defined. We investigated the hypothesis that vesical pacing of the OAB might improve not only the vesical electric activity but also the symptoms. METHODS Vesical pacing was used in 9 patients (age 39.2 +/- 10.3; 5 women, 4 men) with OAB. Under anesthesia, the pacemaker was implanted in an inguinal subcutaneous pocket and connected to 2 pacing electrodes implanted into the vesical vault. The normalization of the waves was tested by 2 recording electrodes which were temporarily applied to the vesical wall and removed post-testing. The pacemaker was then programmed for home pacing to be activated at given times. RESULTS Vesical pacing effected normalization of the dysrhythmic electric waves with disappearance of the OAB symptoms in 7 patients and failed in 2. Vesical pacing was abandoned in 3/7 patients after a few months following the spontaneous disappearance of the symptoms. CONCLUSIONS Vesical pacing has normalized the dysrhythmic electric activity and suppressed the symptoms of the OAB in 77.7% of patients. The pacemaker was removed in 5 patients: 2 failures and 3 after spontaneous waves normalization. No complications were encountered. Vesical pacing is suggested as a treatment for OAB when commonly used therapeutic modalities have failed.
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Affiliation(s)
- Ahmed Shafik
- Department of Surgery and Experimental Research, Faculty of Medicine, Cairo University, Cairo, Egypt.
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Fintl C, Pearson GT, Ricketts SW, Mayhew IG, Hudson NPH. The development and distribution of the interstitial cells of Cajal in the intestine of the equine fetus and neonate. J Anat 2004; 205:35-44. [PMID: 15255960 PMCID: PMC1571323 DOI: 10.1111/j.0021-8782.2004.00315.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
This study set out to determine the pattern of development and distribution of the interstitial cells of Cajal (ICC) in the intestinal tract of the equine fetus and neonate. Intestinal tissue samples from 12 naturally aborted equine fetuses and three euthanized neonates were collected and fixed in formalin prior to applying standard immunohistochemical labelling techniques targeting the c-Kit protein of the ICC. At 6 months of gestation, a network of ICC was present in the myenteric plexus region of both the small and the large intestine. ICC were also present within the circular muscle layer. In the large intestine, a proximal to distal gradient of distribution was evident, with few ICC observed in the more distal parts of the large intestine in the younger fetuses compared with the near-term animals. A transmural gradient of distribution was also evident within the large intestine, with the most luminal part of the muscularis externa being the last area to be colonized by ICC. This region did not appear fully developed until the early neonatal period. An increased density of ICC was noted throughout the large intestine in the regions of the taenial bands in all animals. This study is the first to describe ICC development and distribution in the equine fetus and neonate.
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Affiliation(s)
- C Fintl
- Gastrointestinal Motility and Disease Laboratory, Royal (Dick) School of Veterinary Studies, University of Edinburgh, UK
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Shafik A, El-Sibai O, Shafik AA, Ahmed I. The electrovesicogram in the overactive bladder: role in determining pathogenesis and diagnostic significance. ACTA ACUST UNITED AC 2004; 32:290-3. [PMID: 15045478 DOI: 10.1007/s00240-004-0412-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2003] [Accepted: 02/23/2004] [Indexed: 10/26/2022]
Abstract
We investigated the hypothesis that the abnormal contractility of the smooth musculature of the overactive bladder (OAB) may be due to derangement of its electrical activity. Percutaneous electrovesicography was performed in 22 patients (mean age 46.3 years, 12 men, ten women) with OAB and 14 healthy volunteers (mean age 45.6 years, eight men, six women). Recording was performed with the bladder full and empty. Three electrodes were applied suprapubically and one reference electrode was applied to a lower limb. Reproducible regular triphasic slow waves (SWs) were recorded in the volunteers. The pattern of the full and empty bladder were similar except for the higher amplitude of the waves in the former (P < 0.05). The OAB patients showed a "dysrhythmic" pattern with irregular frequency, amplitude and conduction velocity in both the empty and full bladders. We obtained tachyrhythmic, bradyrhythmic and arrhythmic areas in the same recording. The OAB exhibited a "dysrhythmic" electrical pattern with areas of different electrical activity in the same recording. The tachyrhythmic, bradyrhythmic and arrhythmic areas are suggested to explain the abnormal vesical contractions and clinical manifestations of OAB. Further studies are required to investigate the cause of the dysrhythmic pattern and the electrovesicogram is suggested as an investigative tool in OAB diagnosis.
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Affiliation(s)
- Ahmed Shafik
- Department of Surgery and Experimental Research, Faculty of Medicine, Cairo University, Cairo, Egypt.
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Wang XY, Paterson C, Huizinga JD. Cholinergic and nitrergic innervation of ICC-DMP and ICC-IM in the human small intestine. Neurogastroenterol Motil 2003; 15:531-43. [PMID: 14507353 DOI: 10.1046/j.1365-2982.2003.00429.x] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
With functional evidence emerging that interstitial cells of Cajal (ICC) play a role in smooth muscle innervation, detailed knowledge is needed about the structural aspects of enteric innervation of the human gut. Conventional electronmicroscopy (EM), immunohistochemistry and immuno-EM were performed on the musculature of the distal human ileum focusing on ICC associated with the deep muscular plexus (ICC-DMP) and intramuscular ICC (ICC-IM). ICC-DMP could be identified by EM but not by c-Kit immunohistochemistry. Immuno-EM revealed that ICC-DMP were innervated by both cholinergic and nitrergic nerves, and were the only cells to possess specialized synapse-like junctions with nerve varicosities and gap junction contacts with smooth muscle cells. c-Kit positive ICC near the deep muscular plexus were not ICC-DMP, but ICC-IM located in septa. ICC-IM were innervated by both cholinergic and nitrergic nerves but without specialized contacts. Varicosities of both nerve types were also found scattered throughout the musculature without specialized contact with any ICC. No ICC showed immunoreactivity for neuronal nitric oxide synthase. As ICC-DMP form synapse-like junctions with cholinergic and nitrergic nerves and gap junction contacts with muscle cells, it is hypothesized that ICC-DMP hold a specialized function related to innervation of smooth muscle of the human intestine.
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Affiliation(s)
- X-Y Wang
- Intestinal Disease Research Program, McMaster University, Hamilton, Ontario, Canada
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Jain D, Moussa K, Tandon M, Culpepper-Morgan J, Proctor DD. Role of interstitial cells of Cajal in motility disorders of the bowel. Am J Gastroenterol 2003; 98:618-24. [PMID: 12650797 DOI: 10.1111/j.1572-0241.2003.07295.x] [Citation(s) in RCA: 82] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Idiopathic intestinal pseudo-obstruction is characterized by the failure of the intestinal tract to propel its contents appropriately. This leads to signs and symptoms of bowel obstruction and, in the absence of an associated systemic disorder or the administration of drugs known to result in bowel dysmotility, is termed chronic idiopathic intestinal pseudo-obstruction (CIIP). Histopathologically, patients with CIIP can be characterized as having either myopathic or neuropathic forms, but the large majority of patients do not show any specific histological changes. Interstitial cells of Cajal (ICC) have been shown to be the pacemaker cells of the bowel and have been implicated in the pathogenesis of CIIP. The aim of this study was to compare the number and distribution patterns of c-kit+ ICC in CIIP in patients with mechanical bowel obstruction, other bowel motility disorders, and normal controls. METHODS Six patients with CIIP, six age-matched normal controls, nine patients with mechanical bowel obstruction, and 18 patients with other motility disorders (non-CIIP), including 10 with secondary intestinal pseudo-obstruction, were studied. Toluidine blue, Masson's trichrome, and S-100 immunostaining were performed in all subjects. The ICC were identified by an indirect immunoperoxidase method using a polyclonal c-kit antibody. RESULTS All six patients with CIIP showed total absence of c-kit+ ICC. A subject with neonatal meconium ileus in the non-CIIP group showed patchy areas devoid of c-kit+ ICC amid normal areas. The c-kit+ ICC had a normal number and distribution pattern in all patients with mechanical obstruction and in the remaining 17 non-CIIP subjects. CONCLUSIONS It seems that CIIP is characterized by a total loss of c-kit+ ICC. ICC may play an important role in the etiopathogenesis of CIIP and transient neonatal meconium syndrome, and staining for c-kit receptor may be very useful in the evaluation of motility disorders of the bowel.
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Affiliation(s)
- Dhanpat Jain
- Department of Anatomic Pathology, Program in Gastrointestinal Pathology, Yale University School of Medicine, New Haven, Connecticut, USA
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Rumessen JJ, Vanderwinden JM. Interstitial Cells in the Musculature of the Gastrointestinal Tract: Cajal and Beyond. ACTA ACUST UNITED AC 2003; 229:115-208. [PMID: 14669956 DOI: 10.1016/s0074-7696(03)29004-5] [Citation(s) in RCA: 79] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Expression of the receptor tyrosine kinase KIT on cells referred to as interstitial cells of Cajal (ICC) has been instrumental during the past decade in the tremendous interest in cells in the interstitium of the smooth muscle layers of the digestive tract. ICC generate the pacemaker component (electrical slow waves of depolarization) of the smooth musculature and are involved in neurotransmission. By integration of ICC functions, substantial progress has been made in our understanding of the neuromuscular control of gastrointestinal motility, opening novel therapeutic perspectives. In this article, the ultrastructure and light microscopic morphology, as well as the functions and the development of ICC and of neighboring fibroblast-like cells (FLC), are critically reviewed. Directions for future research are considered and a unifying concept of mesenchymal cells, either KIT positive (the "ICC") or KIT negative "non-Cajal" (including the FLC and possibly also other cell types) cell types in the interstitium of the smooth musculature of the gastrointestinal tract, is proposed. Furthermore, evidence is accumulating to suggest that, as postulated by Santiago Ramon y Cajal, the concept of interstitial cells is not likely to be restricted to the gastrointestinal musculature.
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Affiliation(s)
- Jüri J Rumessen
- Department of Gastroenterology, Hvidovre Hospital, Hvidovre, Denmark
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Rolle U, Piotrowska AP, Nemeth L, Puri P. Altered distribution of interstitial cells of Cajal in Hirschsprung disease. Arch Pathol Lab Med 2002; 126:928-933. [PMID: 12171490 DOI: 10.5858/2002-126-0928-adoico] [Citation(s) in RCA: 80] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
CONTEXT Constipation or recurrent intestinal dysmotility problems are common after definitive surgical treatment in Hirschsprung disease (HD). c-Kit-positive interstitial cells of Cajal (ICCs) play a key role in the motility function and development of the gastrointestinal tract. Interstitial cells of Cajal that carry the tyrosine kinase receptor (c-Kit) develop as either myenteric ICCs or muscular ICCs under the influence of the kit ligand, which can be provided by neuronal and nonneuronal cells, for example, smooth muscle cells. OBJECTIVE To investigate the distribution of myenteric and muscular ICCs in different parts of the colon in HD. METHODS Resected bowel specimens from 8 patients with rectosigmoid HD were investigated using combined staining with c-Kit enzyme and fluorescence immunohistochemistry and acetylcholinesterase and nicotinamide adenine dinucleotide phosphate (NADPH) histochemistry in whole-mount preparations and conventional frozen sections. RESULTS In the normal bowel, ICCs formed a dense network surrounding the myenteric plexus and at the innermost part of the circular muscle. Myenteric ICCs were absent or sparse in the aganglionic bowel and sparse in the transitional zone. The expression of myenteric ICCs in the ganglionic bowel in HD was reduced compared to that in the normal bowel, and they formed only sparse networks. Muscular ICCs were found in the aganglionic bowel, transitional zone, and normoganglionic bowel of HD in a reduced density compared to the normal bowel. CONCLUSION This study demonstrates altered distribution of ICCs in the entire resected bowel of HD patients. This finding suggests that persistent dysmotility problems after pull-through operation in HD may be due to altered distribution and impaired function of ICCs.
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Affiliation(s)
- Udo Rolle
- Children's Research Centre, Our Lady's Hospital for Sick Children, Dublin, Ireland
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Adegboyega PA, Mifflin RC, DiMari JF, Saada JI, Powell DW. Immunohistochemical study of myofibroblasts in normal colonic mucosa, hyperplastic polyps, and adenomatous colorectal polyps. Arch Pathol Lab Med 2002; 126:829-36. [PMID: 12088453 DOI: 10.5858/2002-126-0829-isomin] [Citation(s) in RCA: 114] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
CONTEXT Myofibroblasts are distinct cells with characteristics of both smooth muscle cells and fibroblasts. Through their ability to secrete cytokines, chemokines, prostaglandins, growth factors, and matrix components, they are thought to play critical roles in inflammation, growth, repair, and neoplasia. OBJECTIVE The goal of this study was to identify the distinct cell populations of the lamina propria of normal colon and colorectal polyps. DESIGN We studied the expression of alpha-smooth muscle actin (alphaSMA), smooth muscle myosin (SMM), desmin, vimentin, and c-kit by intestinal mesenchymal (stromal) cells in the normal colonic mucosa (n = 5), as well as in hyperplastic polyps (n = 5), sporadic colorectal adenomas (n = 47), and adenomas from patients with familial polyposis (n = 36). RESULTS In the normal colonic mucosa, the pericryptal stromal cells were alphaSMA+, SMM+, desmin-, and vimentin+, defining them as myofibroblasts. In contrast, cells of the muscularis mucosae were alphaSMA+, SMM+, desmin+, and vimentin-, defining them as smooth muscle cells. alpha-Smooth muscle actin also highlighted direct connections between the muscularis mucosae and the pericryptal myofibroblasts, and vimentin immunostaining showed a network of connections between the alphaSMA+ pericryptal myofibroblasts and the alphaSMA- fibroblasts in the interstitium. In all hyperplastic polyps and adenomatous polyps, the interstitial stromal cells (fibroblasts) now also express alphaSMA and form a syncytium of alphaSMA+ networklike connections throughout the lamina propria. Stromal cells of sporadic adenomas demonstrated the same immunohistochemical staining characteristics displayed by adenomas from patients with familial polyposis and by hyperplastic polyps. Conclusions.-These findings indicate that in normal colon, alphaSMA- fibroblasts are the predominant cell type in the lamina propria. However, the pericryptal (subepithelial) stromal cells are a distinct cell type (alphaSMA+ myofibroblast) that is immunophenotypically different from muscularis mucosae smooth muscle cells and are connected to the interstitial, nonpericryptal fibroblasts with which they exist as a network throughout the lamina propria of the normal colon. Furthermore, in both hyperplastic and neoplastic polyps, there are changes in nonpericryptal fibroblasts from vimentin+, alphaSMA-, and SMM- to vimentin+, alphaSMA+, and SMM+; thus, the interstitial fibroblasts are replaced by myofibroblasts. The factors that cause these changes and the origin of the myofibroblasts need to be determined to clarify the biology of colorectal tumorigenesis.
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Affiliation(s)
- Patrick A Adegboyega
- Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA.
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Schoenberg RA, Kluth D. Experimental small bowel obstruction in chick embryos: Effects on the developing enteric nervous system. J Pediatr Surg 2002; 37:735-40. [PMID: 11987090 DOI: 10.1053/jpsu.2002.32267] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
BACKGROUND/PURPOSE After surgical repair of congenital small bowel atresias, intestinal motility disorders often are observed. These may be caused by changes in the enteric nervous system (ENS) secondary to obstruction. To assess these changes, small bowel atresias were induced experimentally in chick embryos. METHODS On day 11, the small intestines of 90 chicken embryos were ligated microsurgically in ovo. Breeding of the eggs was continued until day 19. The small bowel was removed, fixed, and embedded for silver-staining, semithin serial sections, and transmission electron microscopy. Additionally, acetyl-cholinesterase (AChE)-staining was performed. Normal chick embryos of the same age served as controls. RESULTS Macroscopically, experimentally induced small bowel atresias had the same characteristics as human newborns. Microscopically, the wall structure was preserved; however, the ENS differed markedly from controls. Both proximal and distal to the obstruction, the submucosal plexus was almost completely absent, whereas the myententeric plexus was diminished only in the proximal dilated blind pouch. The axonal net was disrupted additionally. Ganglion cells of the myenteric plexus in the proximal segment were arranged in longitudinal clusters of densely packed cells. In the distal segment ganglion cells formed round clusters. The cells of Cajal, which normally surround the myenteric ganglia, were absent in the proximal and distal segments. CONCLUSIONS In our experiments, structural changes in the ENS could be observed secondary to experimentally induced small bowel atresias in the chick. Because of the lack of ischemia in this model, the main cause of these ENS changes seems to be the dilatation oft the proximal gut. Dilatations are common features in intestinal atresias, anorectal malformations, and Hirschsprung's disease. Our observations, thus, explain motility disorders after the surgical repair of these diseases.
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Porcher C, Baldo M, Henry M, Orsoni P, Julé Y, Ward SM. Deficiency of interstitial cells of Cajal in the small intestine of patients with Crohn's disease. Am J Gastroenterol 2002; 97:118-25. [PMID: 11808934 DOI: 10.1111/j.1572-0241.2002.05430.x] [Citation(s) in RCA: 79] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Interstitial cells of Cajal are critical for the generation of electrical slow waves that regulate the phasic contractile activity of the tunica muscularis of the GI tract. Under certain pathophysiological conditions loss of interstitial cells of Cajal may play a role in the generation of certain motility disorders. The aim of the present study was to determine if there is an abnormality in the density or distribution of interstitial cells of Cajal from patients with Crohn's disease. METHODS Small intestines from control subjects and patients with Crohn's disease were examined using immunohistochemistry and antibodies against the Kit receptor, which is expressed in interstitial cells of Cajal within the tunica muscularis of the GI tract. The density and distribution of interstitial cells of Cajal were assessed in the longitudinal and circular muscle layers and in the myenteric and deep muscular plexus regions of Crohn's and control tissues. RESULTS Tissues from Crohn's disease patients showed an almost complete abolition of interstitial cells of Cajal within the longitudinal and circular muscle layers and a significant reduction in numbers at the level of the myenteric and deep muscular plexuses. CONCLUSIONS In tissues from Crohn's disease patients, the density of interstitial cells of Cajal was reduced throughout the tunica muscularis in comparison to control small intestines. The disturbance of intestinal motility that occurs in patients with Crohn's disease may be a consequence of the loss of or defects in specific populations of interstitial cells of Cajal within the tunica muscularis.
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Affiliation(s)
- Christophe Porcher
- Department of Physiology and Neurophysiology, CNRS-ESA 6034, Faculé des Sciences de Saint-Jérĵme, Marseille, France
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Nemeth L, Puri P. Three-dimensional morphology of c-Kit-positive cellular network and nitrergic innervation in the human gut. Arch Pathol Lab Med 2001; 125:899-904. [PMID: 11419974 DOI: 10.5858/2001-125-0899-tdmock] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
CONTEXT -c-Kit-positive interstitial cells of Cajal (ICC) appear to play a key role in the normal motility function and development of intestine. Nitric oxide is considered to be the most important messenger of inhibitory nonadrenergic, noncholinergic nerves in the enteric nervous system. OBJECTIVES The aims of this study were to examine the distribution of nitrergic innervation and ICCs in normal human bowel and to demonstrate interconnections between ICCs and nitrergic nerves and smooth muscle fibers using histochemical and immunohistochemical double-staining methods with a whole-mount preparation technique and confocal laser scanning microscopy. METHODS Full-thickness small and large bowel specimens were obtained at autopsy from 18 children who died of nongastrointestinal diseases. A whole-mount preparation was performed for all specimens, and double staining was carried out with nicotinamide adenine dinucleotide phosphate (reduced form, NADPH)-diaphorase and c-Kit immunohistochemistry. Double immunofluorohistochemistry with neuronal nitric oxide synthase and c-Kit using confocal laser scanning microscopy was also performed in all specimens. RESULTS The whole-mount preparation facilitated 3-dimensional visualization of the meshlike network of NADPH-diaphorase-positive nerve fibers in the myenteric plexus surrounded by a reticular network of c-Kit-positive ICCs. The dense c-Kit-positive cellular network located between longitudinal and circular muscle layers and at the innermost part of circular muscle layer intermingled with the myenteric plexus. Short, fine processes of ICCs made connections with the muscle fibers and c-Kit-positive cells. CONCLUSIONS The development of double-NADPH-diaphorase histochemistry and c-Kit immunohistochemistry staining technique in a whole-mount preparation provides an easy and useful method for investigating the association between c-Kit-positive cellular network and nitrergic neuronal network in the human bowel wall. The characteristic profiles of the c-Kit-positive cellular network and nitrergic neuronal network and their relationship with the smooth muscle fibers provide a morphologic basis for investigating intestinal motility disorders.
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Affiliation(s)
- L Nemeth
- Children's Research Centre, Our Lady's Hospital for Sick Children, Dublin, Ireland
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Cheng W, Lui VC, Chen QM, Tam PK. Enteric nervous system, interstitial cells of cajal, and smooth muscle vacuolization in segmental dilatation of jejunum. J Pediatr Surg 2001; 36:930-5. [PMID: 11381429 DOI: 10.1053/jpsu.2001.23979] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND/PURPOSE The etiology of congenital segmental dilatation (CSD) of bowel remains elusive. Intestitial cell of Cajal plays a role in the pace making of the intestine. Its abnormality has been documented in a variety of conditions of abnormal intestinal motility. The current study attempts to evaluate the roles of intestitial cells of Cajal, enteric nervous system, and smooth muscle in segmental dilatation of small bowel. METHODS Resected specimen from a neonate with segmental dilatation of jejunum was stained with H&E, Alcian blue, Periodic Acid-Schiff (PAS), and immunostained with S100, Ret, MAP5, and c-kit antibodies using the standard immunohistochemical process. RESULTS The immunostaining of S100, Ret, MAP5 and c-kit of CSD specimen were positive. Localized vacuolization was, however, detected in the circular smooth muscle of the jejunum. The Alcian blue and PAS staining of the vacuolization were negative. CONCLUSIONS CSD shows no abnormality in the enteric nervous system and pace makers. Localized vacuolization suggests myopathy to be a contributing factor to the disease. J Pediatr Surg 36:930-935.
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Affiliation(s)
- W Cheng
- Division of Pediatric Surgery, Department of Surgery, The Hong Kong University Medical Centre, Queen Mary Hospital, Hong Kong, SAR, China
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Huizinga JD, Berezin I, Sircar K, Hewlett B, Donnelly G, Bercik P, Ross C, Algoufi T, Fitzgerald P, Der T, Riddell RH, Collins SM, Jacobson K. Development of interstitial cells of Cajal in a full-term infant without an enteric nervous system. Gastroenterology 2001; 120:561-7. [PMID: 11159897 DOI: 10.1053/gast.2001.21200] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The relationship between the development of the enteric nervous system and interstitial cells of Cajal (ICC) in the human small intestine was investigated in a full-term infant who presented with intestinal pseudo-obstruction. Immunohistochemistry revealed absence of enteric nerves and ganglia but abundant c-Kit immunoreactivity associated with Auerbach's plexus (ICC-AP). However, c-Kit immunoreactivity associated with the deep muscular plexus (ICC-DMP) and intermuscular ICC was absent. Electron microscopy showed ICC-AP with a normal ultrastructure; ICC-DMP were seen but were severely injured, suggesting degeneration. In vitro recording of intestinal muscle showed slow wave activity as well as response to cholinergic stimulation. Fluoroscopic examination of the small bowel showed a variety of motor patterns, including rhythmic, propagating contractions. In conclusion, total absence of enteric nerves was associated with absence of normal ICC-DMP. However, a normal musculature, including a network of ICC-AP, allowed for generation of rhythmic, propagating contractile activity, suggesting the presence of functional motor activity.
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Affiliation(s)
- J D Huizinga
- Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
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Ohshiro K, Yamataka A, Kobayashi H, Hirai S, Miyahara K, Sueyoshi N, Suda K, Miyano T. Idiopathic gastric perforation in neonates and abnormal distribution of intestinal pacemaker cells. J Pediatr Surg 2000; 35:673-6. [PMID: 10813320 DOI: 10.1053/jpsu.2000.5940] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND/PURPOSE The etiology of idiopathic gastric perforation (IGP) in neonates is unclear. Interstitial cells of Cajal (ICC) express tyrosine kinase receptor C-kit, and act as gastrointestinal pacemaker cells. Stem cell factor (SCF) is a C-kit ligand and plays an important role in immune system homeostasis in the gastrointestinal tract. The authors hypothesized that abnormal distribution of ICC or SCF in the gastric wall (ie, abnormal motility or impaired immunity) could predispose the stomach to IGP. METHODS Stomachs obtained at postmortem from neonates who died of IGP (n = 7) and other causes (control group; n = 10) were used. Biopsy sections were taken at random from various sites in the stomach, including macroscopically intact areas, and labeled immunohistochemically using antibodies to C-kit(a marker for ICC) and SCF. RESULTS In all control specimens, ICC were present between the muscle layers and around the myenteric plexuses of the stomach wall. In contrast, ICC were absent in all biopsy sections from 3 of the 7 IGP stomachs. In the remaining 4 IGP stomachs, there were fewer ICC in the muscle layers compared with controls, and ICC were absent around the myenteric plexuses. The distribution of SCF immunoreactivity in IGP and control specimens was similar. CONCLUSION The findings suggest that a lack of ICC (ie, gastric hypomotility) may be implicated in the etiology of IGP in neonates.
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Affiliation(s)
- K Ohshiro
- Department of Pediatric Surgery, Juntendo University School of Medicine, Tokyo, Japan
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