X Y Wang

Publications (12)47.97 Total impact

• Article: Role of interstitial cells of Cajal in the generation and modulation of motor activity induced by cholinergic neurotransmission in the stomach.

  R-X Zhang, X-Y Wang, D Chen, J D Huizinga
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  ABSTRACT: Interstitial cells of Cajal (ICC) are intimately linked to the enteric nervous system and a better understanding of the interactions between the two systems is going to advance our understanding of gut motor control. The objective of the present study was to investigate the role of ICC in the generation of gastric motor activity induced by cholinergic neurotransmission. Gastric motor activity was evoked through activation of intrinsic cholinergic neural activity, in in vitro muscle strips by electrical field stimulation, in the in vitro whole stomach by distension and in vivo by fluoroscopy after gavaging the stomach with barium sulfate. The cholinergic activity was assessed as that component of the effect of the stimulus that was sensitive to atropine. These experiments were carried out in wild-type and Ws/Ws rats that have few intramuscular ICC (ICC-IM) in the stomach. Key Under all three experimental conditions, cholinergic activity was prominent in both wild-type and W mutant rats providing evidence against the hypothesis that cholinergic neurotransmission to smooth muscle is primarily mediated by ICC-IM. Strong cholinergic activity in Ws/Ws rats was not due to upregulation of muscarinic receptors in ICC but possibly in smooth muscle of the antrum. Pacemaker ICC play a prominent role in the expression of motor activity induced by cholinergic activity and our data suggest that cholinergic neurotransmission to ICC affects the pacemaker frequency.
  Neurogastroenterology and Motility 09/2011; 23(9):e356-71. · 3.41 Impact Factor
• Article: Igf1r+/CD34+ immature ICC are putative adult progenitor cells, identified ultrastructurally as fibroblast‐like ICC in Ws/Ws rat colon

  X.Y. Wang, E. Albertí, E.J. White, H.B. Mikkelsen, J.O. Larsen, M. Jiménez, J.D. Huizinga
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  ABSTRACT: The colon of Ws/Ws mutant rats shows impairment of pacemaker activity and altered inhibitory neurotransmission. The present study set out to find structural correlates to these findings to resolve mechanisms. In the colon of Ws/Ws rats, interstitial cells of Cajal associated with Auerbach’s plexus (ICC-AP) were significantly decreased and ICC located at the submuscular plexus and intramuscular ICC were rarely observed based on immunohistochemistry and electron microscopy. Ultrastructural investigations revealed that there was no overall loss of all types of interstitial cells combined. Where loss of ICC was observed, a marked increase in fibroblast-like ICC (FL-ICC) was found at the level of AP. Immunoelectron microscopy proved FL-ICC to be c-Kit– but gap junction coupled to each other and to c-Kit+ ICC; they were associated with enteric nerves and occupied space normally occupied by ICC in the wild-type rat colon, suggesting them to be immature ICC. In addition, a marked increase in immunoreactivity for insulin-like growth factor 1 receptor (Igf1r) occurred, co-localized with CD34 but not with c-Kit. A significantly higher number of Igf1r+/CD34+ cells were found in Ws/Ws compared to wild-type rat colons. These CD34+/Igf1r+ cells in the Ws/Ws colon occupied the same space as FL-ICC. Hence we propose that a subset of immature ICC (FL-ICC) consists of adult progenitor cells. Immunohistochemistry revealed a reduction of neurons positive for neuronal nitric oxide synthase. The functional capabilities of the immature ICC and the regenerative capabilities of the adult progenitor cells need further study. The morphological features described here show that the loss of pacemaker activity is not associated with failure to develop a network of interstitial cells around AP but a failure to develop this network into fully functional pacemaker cells. The reduction in nitrergic innervation associated with the Ws mutation may be the result of a reduction in nitrergic neurons.
  Journal of Cellular and Molecular Medicine 08/2009; 13(9b):3528 - 3540. · 4.13 Impact Factor
• Source

  Available from: Jan D. Huizinga

  Article: Loss of intramuscular and submuscular interstitial cells of Cajal and associated enteric nerves is related to decreased gastric emptying in streptozotocin-induced diabetes.

  X-Y Wang, J D Huizinga, J Diamond, L W C Liu
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  ABSTRACT: Interstitial cells of Cajal (ICC) are associated with afferent innervation and peristalsis of the stomach suggestive of a key role in the pathophysiology of gastroparesis. We studied changes in the density and ultrastructure of ICC and enteric nerves in the streptozotocin-induced diabetes mellitus (STZ-DM) in Wistar rats using immunohistochemistry and electron microscopy. Gastric emptying was studied in vivo by single-photon emission computed tomography. In the STZ-DM antrum, a marked reduction was observed in the density of the intramuscular ICC (ICC-IM) and ICC located at the submucosal border of the circular muscle layer of the antrum (ICC-SM). The surviving ICC showed lamellar bodies and partial vacuolation of the cytoplasm content, loss of connections between ICC-IM and nerves; it appeared that injured ICC-IM developed into fibroblast-like ICC. ICC associated with Auerbach's plexus (ICC-AP) in the antrum and ICC in the fundus were not affected significantly except for a loss of connections with nerve structures. Marked reduction in nerve tissue (Protein Gene Product-9.5 positivity) was also restricted to the muscle layers including nitrergic nerves (neuronal nitric oxide synthase positivity). In vivo assessed gastric emptying was markedly reduced in STZ-DM rats. Our data demonstrate in the STZ-DM rat stomach a decreased density of ICC limited to the antrum and to ICC-IM and ICC-SM, and structural degeneration in ICC-IM and associated nerves with a special emphasis on loss of synaptic connections, accompanied by a decrease in gastric emptying. Hence, in this model of gastroparetic diabetes, regional injury to subsets of ICC and nerves are associated with gastric motor dysfunction.
  Neurogastroenterology and Motility 07/2009; 21(10):1095-e92. · 3.41 Impact Factor
• Source

  Available from: Jytte overgaard Larsen

  Article: Igf1r+/CD34+ immature ICC are putative adult progenitor cells, identified ultrastructurally as fibroblast-like ICC in Ws/Ws rat colon.

  X Y Wang, E Albertí, E J White, H B Mikkelsen, J O Larsen, M Jiménez, J D Huizinga
  [show abstract] [hide abstract]
  ABSTRACT: The colon of Ws/Ws mutant rats shows impairment of pacemaker activity and altered inhibitory neurotransmission. The present study set out to find structural correlates to these findings to resolve mechanisms. In the colon of Ws/Ws rats, interstitial cells of Cajal associated with Auerbach's plexus (ICC-AP) were significantly decreased and ICC located at the submuscular plexus and intramuscular ICC were rarely observed based on immunohistochemistry and electron microscopy. Ultrastructural investigations revealed that there was no overall loss of all types of interstitial cells combined. Where loss of ICC was observed, a marked increase in fibroblast-like ICC (FL-ICC) was found at the level of AP. Immunoelectron microscopy proved FL-ICC to be c-Kit(-) but gap junction coupled to each other and to c-Kit(+) ICC; they were associated with enteric nerves and occupied space normally occupied by ICC in the wild-type rat colon, suggesting them to be immature ICC. In addition, a marked increase in immunoreactivity for insulin-like growth factor 1 receptor (Igf1r) occurred, co-localized with CD34 but not with c-Kit. A significantly higher number of Igf1r(+)/CD34(+) cells were found in Ws/Ws compared to wild-type rat colons. These CD34(+)/Igf1r(+) cells in the Ws/Ws colon occupied the same space as FL-ICC. Hence we propose that a subset of immature ICC (FL-ICC) consists of adult progenitor cells. Immunohistochemistry revealed a reduction of neurons positive for neuronal nitric oxide synthase. The functional capabilities of the immature ICC and the regenerative capabilities of the adult progenitor cells need further study. The morphological features described here show that the loss of pacemaker activity is not associated with failure to develop a network of interstitial cells around AP but a failure to develop this network into fully functional pacemaker cells. The reduction in nitrergic innervation associated with the Ws mutation may be the result of a reduction in nitrergic neurons.
  Journal of Cellular and Molecular Medicine 03/2009; 13(9B):3528-40. · 4.13 Impact Factor
• Source

  Available from: Jan D. Huizinga

  Article: Ultrastructural evidence for communication between intramuscular vagal mechanoreceptors and interstitial cells of Cajal in the rat fundus.

  T L Powley, X-Y Wang, E A Fox, R J Phillips, L W C Liu, J D Huizinga
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  ABSTRACT: To assess whether afferent vagal intramuscular arrays (IMAs), putative gastrointestinal mechanoreceptors, form contacts with interstitial cells of Cajal of the intramuscular type (ICC-IM) and to describe any such contacts, electron microscopic analyses were performed on the external muscle layers of the fundus containing dextran-labelled diaminobenzidin (DAB)-stained IMAs. Special staining and embedding techniques were developed to preserve ultrastructural features. Within the muscle layers, IMA varicosities were observed in nerve bundles traversing major septa without contact with ICC-IM, contacting unlabelled neurites and glial cells. IMA varicosities were encountered in minor septa in contact with ICC-IM which were not necessarily in close contact with muscle cells. In addition, IMA varicosities were observed within muscle bundles in close contact with ICC-IM which were in gap junction contact with muscle cells. IMAs formed varicosities containing predominantly small agranular vesicles, occasionally large granular vesicles and prejunctional thickenings in apposition to ICC-IM processes, indicating communication between ICC and IMA via synapse-like contacts. Taken together, these different morphological features are consistent with a hypothesized mechanoreceptor role for IMA-ICC complexes. Intraganglionic laminar ending varicosities contacted neuronal somata and dendrites in the myenteric plexus of the fundus, but no contacts with ICC associated with Auerbach's plexus were encountered.
  Neurogastroenterology and Motility 02/2008; 20(1):69-79. · 3.41 Impact Factor
• Article: Pacemaker activity and inhibitory neurotransmission in the colon of Ws/Ws mutant rats.

  E Albertí, H B Mikkelsen, X Y Wang, M Díaz, J O Larsen, J D Huizinga, M Jiménez
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  ABSTRACT: The aim of this study was to characterize the pacemaker activity and inhibitory neurotransmission in the colon of Ws/Ws mutant rats, which harbor a mutation in the c-kit gene that affects development of interstitial cells of Cajal (ICC). In Ws/Ws rats, the density of KIT-positive cells was markedly reduced. Wild-type, but not Ws/Ws, rats showed low- and high-frequency cyclic depolarization that were associated with highly regular myogenic motor patterns at the same frequencies. In Ws/Ws rats, irregular patterns of action potentials triggered irregular muscle contractions occurring within a bandwidth of 10-20 cycles/min. Spontaneous activity of nitrergic nerves caused sustained inhibition of muscle activity in both wild-type (+/+) and Ws/Ws rats. Electrical field stimulation of enteric nerves, after blockade of cholinergic and adrenergic activity, elicited inhibition of mechanical activity and biphasic inhibitory junction potentials both in wild-type and Ws/Ws rats. Apamin-sensitive, likely purinergic, inhibitory innervation was not affected by loss of ICC. Variable presence of nitrergic innervation likely reflects the presence of direct nitrergic innervation to smooth muscle cells as well as indirect innervation via ICC. In summary, loss of ICC markedly affects pacemaker and motor activities of the rat colon. Inhibitory innervation is largely maintained but nitrergic innervation is reduced possibly related to the loss of ICC-mediated relaxation.
  AJP Gastrointestinal and Liver Physiology 07/2007; 292(6):G1499-510. · 3.43 Impact Factor
• Source

  Available from: Pere Clavé

  Article: Interstitial cells of Cajal and neuromuscular transmission in the rat lower oesophageal sphincter.

  R Farré, X-Y Wang, E Vidal, A Domènech, M Pumarola, P Clave, J D Huizinga, M Jiménez
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  ABSTRACT: The distribution of interstitial cells of Cajal (ICC) and neurotransmission were investigated in lower oesophageal sphincter (LES) circular muscle strips from Sprague-Dawley (SD) rats, Ws/Ws mutant rats and their wild-type (+/+) siblings. Intramuscular c-Kit-positive cells, confirmed to be ICC-IM by electron microscopy, were observed throughout both muscle layers from SD and +/+ rats. In contrast, c-Kit-positive, ultrastructurally typical ICC-IM were absent in Ws/Ws. LES strips from Ws/Ws rats showed increased spontaneous contractile activity. Strips from SD and +/+ rats, responded to electrical neuronal stimulation with a relaxation that was in part L-NNA and in part apamin sensitive, followed by a contraction which was decreased by atropine. In Ws/Ws rats, similar to +/+ rats, neurally mediated relaxation was L-NNA and apamin sensitive and the contraction was decreased by atropine. We conclude that in the rat LES, relaxation is mediated by NO and an apamin-sensitive mediator, and contraction primarily by acetylcholine. Despite the absence of c-Kit-positive ICC, nerve-muscle interaction can be accomplished likely by diffusion of neurotransmitters to the smooth muscle cells. The lack of c-Kit-positive ICC is related to an increase in the basal tone and spontaneous contractile activity. The presence of fibroblast-like ICC in Ws/Ws rats might represent immature ICC whose possible functions need further investigation.
  Neurogastroenterology and Motility 07/2007; 19(6):484-96. · 3.41 Impact Factor
• Source

  Available from: Jan D. Huizinga

  Article: Ultrastructural injury to interstitial cells of Cajal and communication with mast cells in Crohn's disease.

  X-Y Wang, N Zarate, J D Soderholm, J M Bourgeois, L W C Liu, J D Huizinga
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  ABSTRACT: Crohn's disease associated dysmotility has been attributed to fibrosis and damage to enteric nerves but injury to interstitial cells of Cajal (ICC) could also be involved. We assessed ICC in specimens obtained from patients with Crohn's disease and determined the relation between ICC and the inflammatory infiltrate, particularly mast cells (MC) using quantitative immunohistochemistry and electron microscopy. Ultrastructural injury to ICC was patchy in all ICC subtypes but ICC-Auerbach's plexus (AP) showed damage more frequently, i.e. swelling of mitochondria, decreased electron density, autophagosomes and partial depletion of the cytoplasm. Light microscopy confirmed a significant decrease in c-kit immunoreactivity for ICC-AP and an increased number of MC in the muscularis externa. Electron microscopy showed MC exhibiting piecemeal degranulation and making frequent and selective membrane-to-membrane contact with all types of injured ICC which suggests chronic release of granule content to affect ICC. Extent of ICC injury was not associated with duration of the disease. In conclusion, ultrastructural injury and loss of ICC-AP is evident in Crohn's disease. Epidemiological and morphological data suggest that ICC have the capacity to regenerate in spite of the chronic insult. The muscularis hosts a marked number of MC that exhibit piecemeal degranulation associated with ICC and may facilitate ICC maintenance.
  Neurogastroenterology and Motility 06/2007; 19(5):349-64. · 3.41 Impact Factor
• Article: Low doses of ionizing radiation can prevent radiation-induced colonic epithelial hyporesponsiveness to muscarinic agonists.

  N Zarate, X Y Wang, E J White, D Boreham, P K Rangachari, J D Huizinga
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  ABSTRACT: Colonic epithelium hyporesponsiveness to different secretagogues occurs after exposure to ionizing radiation, increasing susceptibility to bacterial translocation and intraluminal toxins. Growing evidence suggests that the biological effects of radiation might be hormetic in nature. We investigated if exposure to low doses of ionizing radiation (LDR) can prevent colon hyposecretion due to subsequent larger doses. Rats were exposed to LDR (0.05 Gy) 24 h prior to 6 Gy, high dose radiation (HDR). The cyclic adenosine monophosphate (cAMP)-mediated pathway was explored using forskolin (FSK) and the intracellular Ca2+-mediated pathway through cholinergic stimulation. Changes in the colonic epithelium at the ultrastructural level were also explored. Maximal short circuit current (Isc) response to carbachol was significantly reduced in the group exposed to 6 Gy HDR and this was completely prevented by prior exposure to LDR. Responses to both FSK and electrical field stimulation (EFS) were significantly reduced after HDR but they were not prevented by prior adaption of LDR. Hyposecretion was not prevented by the inducible nitric oxide synthase (iNOS) inhibitor L-N6-(l-iminoethyl)lysine (L-NIL) ruling out a role for iNOS-derived nitric oxide (NO) in the colonic hyposecretion associated with whole body radiation. Prior exposure to LDR diminished the deleterious effect of full HDR on the ultrastructure of colonic epithelium as colonocytes vacuolization, microvilli lost and separation between neighboring cells were less evident. Previous exposure to LDR can prevent intracellular Ca2+-mediated colonic hyposecretion associated with exposure to HDR but fails to modify cAMP-mediated hyposecretion. Morphological damage at the ultrastructural level is less evident after prior LDR.
  International Journal of Radiation Biology 01/2007; 82(12):887-98. · 2.28 Impact Factor
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  Available from: Gervais Tougas

  Article: Intramuscular interstitial cells of Cajal associated with mast cells survive nitrergic nerves in achalasia.

  N Zarate, X Y Wang, G Tougas, M Anvari, D Birch, F Mearin, J-R Malagelada, J D Huizinga
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  ABSTRACT: Achalasia is dominated by injury to inhibitory nerves. As intramuscular interstitial cells of Cajal (ICC-IM) are proposed to form functional units with nitrergic nerves, their fate in achalasia may be critically important. We studied the relationship between loss of nitrergic nerves and injury to ICC-IM in patients with achalasia and determined associations between ICC-IM and mast cells (MC), using quantitative immunohistochemistry and electron microscopy. Loss of neuronal nitric oxide synthase (nNOS) immunoreactivity was completed within 3 years of acquiring achalasia. Thereafter, progressive ultrastructural injury to remaining nerve structures was evident. Within the first 2 years, the number of ICC-IM did not decline although ultrastructural injury was already present. Thereafter, loss of ICC-IM occurred unrelated to duration of disease. Damage to ICC-IM appeared unrelated to nerve injury. A significant MC infiltration was observed in the musculature; the number of MC was positively related to the persistent number of ICC-IM. Mast cell formed close contacts with ICC-IM and piecemeal-degranulation occurred towards ICC-IM. In conclusion, injury to ICC-IM in achalasia is variable, but not related to duration of disease and injury to nitrergic nerves. MC are prominent and form close functional contact with ICC-IM which may be responsible for their relatively long survival.
  Neurogastroenterology and Motility 08/2006; 18(7):556-68. · 3.41 Impact Factor
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  Available from: Jan D. Huizinga

  Article: Cholinergic and nitrergic innervation of ICC-DMP and ICC-IM in the human small intestine.

  X-Y Wang, C Paterson, J D Huizinga
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  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.
  Neurogastroenterology and Motility 11/2003; 15(5):531-43. · 3.41 Impact Factor
• Article: Severe idiopathic gastroparesis due to neuronal and interstitial cells of Cajal degeneration: pathological findings and management.

  N Zárate, F Mearin, X-Y Wang, B Hewlett, J D Huizinga, J-R Malagelada
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  ABSTRACT: Delayed gastric emptying can be due to muscular, neural, or humoral abnormalities. In the absence of an identified cause, gastroparesis is labelled as idiopathic. We present the case of a patient with severe idiopathic gastroparesis. Pharmacological approaches failed, as well as reduction in gastric emptying resistance with pyloric injection of botulinum toxin and pyloroplasty. Therefore, subtotal gastrectomy was performed. Histological and immunohistochemical study of the resected specimen showed hypoganglionosis, neuronal dysplasia, and a marked reduction in both myenteric and intramuscular interstitial cells of Cajal. To our knowledge, this is the first time these rare histological findings have been described in a patient with idiopathic gastroparesis.
  Gut 08/2003; 52(7):966-70. · 10.11 Impact Factor