{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T14:10:26Z","timestamp":1792937426158,"version":"4.5.0"},"reference-count":111,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2020,6,25]],"date-time":"2020-06-25T00:00:00Z","timestamp":1593043200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001776","name":"University of Western Sydney","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/501100001776","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001036","name":"Australian Rotary Health","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/501100001036","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Millions of patients worldwide suffer from gastrointestinal (GI) motility disorders such as gastroparesis. These disorders typically include debilitating symptoms, such as chronic nausea and vomiting. As no cures are currently available, clinical care is limited to symptom management, while the underlying causes of impaired GI motility remain unaddressed. The efficient movement of contents through the GI tract is facilitated by peristalsis. These rhythmic slow waves of GI muscle contraction are mediated by several cell types, including smooth muscle cells, enteric neurons, telocytes, and specialised gut pacemaker cells called interstitial cells of Cajal (ICC). As ICC dysfunction or loss has been implicated in several GI motility disorders, ICC represent a potentially valuable therapeutic target. Due to their availability, murine ICC have been extensively studied at the molecular level using both normal and diseased GI tissue. In contrast, relatively little is known about the biology of human ICC or their involvement in GI disease pathogenesis. Here, we demonstrate human gastric tissue as a source of primary human cells with ICC phenotype. Further characterisation of these cells will provide new insights into human GI biology, with the potential for developing novel therapies to address the fundamental causes of GI dysmotility.<\/jats:p>","DOI":"10.3390\/ijms21124540","type":"journal-article","created":{"date-parts":[[2020,6,26]],"date-time":"2020-06-26T05:19:36Z","timestamp":1593148776000},"page":"4540","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":127,"title":["Understanding the Biology of Human Interstitial Cells of Cajal in Gastrointestinal Motility"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9224-1199","authenticated-orcid":false,"given":"Daphne","family":"Foong","sequence":"first","affiliation":[{"name":"School of Medicine, Western Sydney University, Campbelltown, NSW 2560, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9741-0318","authenticated-orcid":false,"given":"Jerry","family":"Zhou","sequence":"additional","affiliation":[{"name":"School of Medicine, Western Sydney University, Campbelltown, NSW 2560, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"Zarrouk","sequence":"additional","affiliation":[{"name":"Campbelltown Private Hospital, Campbelltown, NSW 2560, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3127-2933","authenticated-orcid":false,"given":"Vincent","family":"Ho","sequence":"additional","affiliation":[{"name":"School of Medicine, Western Sydney University, Campbelltown, NSW 2560, Australia"},{"name":"Campbelltown Private Hospital, Campbelltown, NSW 2560, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael D.","family":"O\u2019Connor","sequence":"additional","affiliation":[{"name":"School of Medicine, Western Sydney University, Campbelltown, NSW 2560, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,6,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1159\/000092876","article-title":"Gastrointestinal Motility Disorders: An Update","volume":"24","author":"Lacy","year":"2006","journal-title":"Dig. Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"G1","DOI":"10.1152\/ajpgi.90380.2008","article-title":"Gut peristalsis is governed by a multitude of cooperating mechanisms","volume":"296","author":"Huizinga","year":"2009","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1002\/(SICI)1097-0029(19991115)47:4<239::AID-JEMT3>3.0.CO;2-0","article-title":"Gastrointestinal peristalsis: Joint action of enteric nerves, smooth muscle, and interstitial cells of Cajal","volume":"47","author":"Huizinga","year":"1999","journal-title":"Microsc. Res. Tech."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"294","DOI":"10.5056\/jnm14060","article-title":"The significance of interstitial cells in neurogastroenterology","volume":"20","author":"Blair","year":"2014","journal-title":"J. Neurogastroenterol. Motil."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1152\/physrev.00037.2013","article-title":"Interstitial cells: Regulators of smooth muscle function","volume":"94","author":"Sanders","year":"2014","journal-title":"Physiol. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1111\/j.1365-2982.2008.01109.x","article-title":"Interstitial cells of Cajal in health and disease","volume":"20","author":"Farrugia","year":"2008","journal-title":"Neurogastroenterol. Motil."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1111\/j.1365-2559.2006.02493.x","article-title":"Interstitial cells of Cajal in health and disease. Part I: Normal ICC structure and function with associated motility disorders","volume":"50","author":"Streutker","year":"2007","journal-title":"Histopathology"},{"key":"ref_8","first-page":"891","article-title":"Histologie du syste me nerveux de I\u2019Homme et des verte be s","volume":"2","author":"Cajal","year":"1911","journal-title":"Maloine (Paris)"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1113\/jphysiol.2006.116624","article-title":"Structure and organization of interstitial cells of Cajal in the gastrointestinal tract","volume":"576","author":"Komuro","year":"2006","journal-title":"J. Physiol."},{"key":"ref_10","first-page":"157","article-title":"Ultrastructure of the tunica muscularis of the cardial portion of the human esophagus and stomach, with special reference to the so-called Cajal\u2019s interstitial cells","volume":"82","author":"Cortesini","year":"1977","journal-title":"Arch. Ital. Anat. Embriol."},{"key":"ref_11","first-page":"G638","article-title":"Interstitial cells in deep muscular plexus of canine small intestine may be specialized smooth muscle cells","volume":"265","author":"Torihashi","year":"1993","journal-title":"Am. J. Physiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/0016-5085(92)91784-2","article-title":"Ultrastructure of interstitial cells of Cajal associated with deep muscular plexus of human small intestine","volume":"102","author":"Rumessen","year":"1992","journal-title":"Gastroenterology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1417","DOI":"10.1016\/0016-5085(91)70033-T","article-title":"Interstitial Cells of Cajal in Human Small Intestine: Ultrastructural Identification and Organization Between the Main Smooth Muscle Layers","volume":"100","author":"Rumessen","year":"1991","journal-title":"Gastroenterology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1111\/j.1469-7793.2000.t01-1-00355.x","article-title":"Pacemaking in interstitial cells of Cajal depends upon calcium handling by endoplasmic reticulum and mitochondria","volume":"525","author":"Ward","year":"2000","journal-title":"J. Physiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1002\/cne.20746","article-title":"Synaptic specializations exist between enteric motor nerves and interstitial cells of Cajal in the murine stomach","volume":"493","author":"Beckett","year":"2005","journal-title":"J. Comp. Neurol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1393","DOI":"10.1523\/JNEUROSCI.20-04-01393.2000","article-title":"Interstitial cells of Cajal mediate cholinergic neurotransmission from enteric motor neurons","volume":"20","author":"Ward","year":"2000","journal-title":"J. Neurosci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1679\/aohc1950.40.171","article-title":"Electron microscopic studies on the innervation of the smooth muscle and the interstitial cell of Cajal in the small intestine of the mouse and bat","volume":"40","author":"Yamamoto","year":"1977","journal-title":"Arch. Histol. Jpn."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1046\/j.1365-2982.2003.00429.x","article-title":"Cholinergic and nitrergic innervation of ICC-DMP and ICC-IM in the human small intestine","volume":"15","author":"Wang","year":"2003","journal-title":"Neurogastroenterol. Motil."},{"key":"ref_19","first-page":"1153","article-title":"Interstitital cells of Cajal in the human stomach: Distribution and relationship with enteric innervation","volume":"19","author":"Pacini","year":"2004","journal-title":"Histol. Histopathol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"12008","DOI":"10.1073\/pnas.93.21.12008","article-title":"Interstitial cells of Cajal mediate inhibitory neurotransmission in the stomach","volume":"93","author":"Burns","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1515\/bmc-2015-0034","article-title":"Interstitial cells of Cajal and telocytes in the gut: Twins, related or simply neighbor cells?","volume":"7","author":"Chiara","year":"2016","journal-title":"Biomol. Concepts"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1111\/j.1582-4934.2010.01059.x","article-title":"TELOCYTES\u2014A case of serendipity: The winding way from Interstitial Cells of Cajal (ICC), via Interstitial Cajal-Like Cells (ICLC) to TELOCYTES","volume":"14","author":"Popescu","year":"2010","journal-title":"J. Cell. Mol. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1038\/373347a0","article-title":"W\/kit gene required for interstitial cells of Cajal and for intestinal pacemaker activity","volume":"373","author":"Hulzinga","year":"1995","journal-title":"Nature"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1152\/physiolgenomics.00113.2007","article-title":"Differential gene expression in functional classes of interstitial cells of Cajal in murine small intestine","volume":"31","author":"Chen","year":"2007","journal-title":"Physiol. Genom."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"G351","DOI":"10.1152\/ajpgi.00281.2003","article-title":"Immunomagnetic enrichment of interstitial cells of Cajal","volume":"286","author":"Ordog","year":"2004","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"C529","DOI":"10.1152\/ajpcell.2000.279.2.C529","article-title":"Molecular markers expressed in cultured and freshly isolated interstitial cells of Cajal","volume":"279","author":"Epperson","year":"2000","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"C448","DOI":"10.1152\/ajpcell.00273.2003","article-title":"Purification of interstitial cells of Cajal by fluorescence-activated cell sorting","volume":"286","author":"Ordog","year":"2004","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"C497","DOI":"10.1152\/ajpcell.00147.2006","article-title":"Selective labeling and isolation of functional classes of interstitial cells of Cajal of human and murine small intestine","volume":"292","author":"Chen","year":"2007","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/S0016-5085(99)70560-3","article-title":"Blockade of kit signaling induces transdifferentiation of interstitial cells of cajal to a smooth muscle phenotype","volume":"117","author":"Torihashi","year":"1999","journal-title":"Gastroenterology"},{"key":"ref_30","first-page":"97","article-title":"c-kit-dependent development of interstitial cells and electrical activity in the murine gastrointestinal tract","volume":"280","author":"Torihashi","year":"1995","journal-title":"Cell Tissue Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1111\/j.1469-7793.1997.241bc.x","article-title":"Development of electrical rhythmicity in the murine gastrointestinal tract is specifically encoded in the tunica muscularis","volume":"505","author":"Ward","year":"1997","journal-title":"J. Physiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"G1370","DOI":"10.1152\/ajpgi.00074.2009","article-title":"Ano1 is a selective marker of interstitial cells of Cajal in the human and mouse gastrointestinal tract","volume":"296","author":"Gibbons","year":"2009","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4887","DOI":"10.1113\/jphysiol.2009.176198","article-title":"Expression of anoctamin 1\/TMEM16A by interstitial cells of Cajal is fundamental for slow wave activity in gastrointestinal muscles","volume":"587","author":"Hwang","year":"2009","journal-title":"J. Physiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"4905","DOI":"10.1113\/jphysiol.2009.176206","article-title":"A Ca2+-activated Cl\u2013 conductance in interstitial cells of Cajal linked to slow wave currents and pacemaker activity","volume":"587","author":"Zhu","year":"2009","journal-title":"J. Physiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1002\/(SICI)1097-0029(19991115)47:4<267::AID-JEMT5>3.0.CO;2-O","article-title":"Comparative morphology of interstitial cells of Cajal: Ultrastructural characterization","volume":"47","author":"Komuro","year":"1999","journal-title":"Microsc. Res. Tech."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1267\/ahc.06023","article-title":"Interstitial cells of cajal are involved in neurotransmission in the gastrointestinal tract","volume":"39","author":"Iino","year":"2006","journal-title":"Acta Histochem. Cytochem."},{"key":"ref_37","first-page":"139","article-title":"Quantitative analysis by flow cytometry of interstitial cells of Cajal, pacemakers, and mediators of neurotransmission in the gastrointestinal tract","volume":"62","author":"Redelman","year":"2004","journal-title":"Cytom. Part A"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1053\/j.gastro.2008.01.036","article-title":"Progenitors of Interstitial Cells of Cajal in the Postnatal Murine Stomach","volume":"134","author":"Redelman","year":"2008","journal-title":"Gastroenterology"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.1053\/j.gastro.2009.11.007","article-title":"A model to study the phenotypic changes of interstitial cells of Cajal in gastrointestinal diseases","volume":"138","author":"Ro","year":"2010","journal-title":"Gastroenterology"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Lee, M.Y., Ha, S.E., Park, C., Park, P.J., Fuchs, R., Wei, L., Jorgensen, B.G., Redelman, D., Ward, S.M., and Sanders, K.M. (2017). Transcriptome of interstitial cells of Cajal reveals unique and selective gene signatures. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0176031"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1111\/j.1469-7793.1998.203by.x","article-title":"Spontaneous electrical rhythmicity in cultured interstitial cells of cajal from the murine small intestine","volume":"513","author":"Koh","year":"1998","journal-title":"J. Physiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1038\/nm0798-848","article-title":"Interstitial cells of Cajal generate a rhythmic pacemaker current","volume":"4","author":"Thomsen","year":"1998","journal-title":"Nat. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1113\/jphysiol.2004.063875","article-title":"Two types of spontaneous depolarizations in the interstitial cells freshly prepared from the murine small intestine","volume":"559","author":"Goto","year":"2004","journal-title":"J. Physiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"C608","DOI":"10.1152\/ajpcell.00360.2014","article-title":"Intracellular Ca2+ release from endoplasmic reticulum regulates slow wave currents and pacemaker activity of interstitial cells of Cajal","volume":"308","author":"Zhu","year":"2015","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1053\/j.gastro.2007.06.024","article-title":"Septal interstitial cells of Cajal conduct pacemaker activity to excite muscle bundles in human jejunum","volume":"133","author":"Lee","year":"2007","journal-title":"Gastroenterology"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Chen, Y., Shamu, T., Chen, H., Besmer, P., Sawyers, C.L., and Chi, P. (2011). Visualization of the interstitial cells of cajal (ICC) network in mice. J. Vis. Exp., e2802.","DOI":"10.3791\/2802"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1113\/jphysiol.1994.sp020343","article-title":"Mutation of the proto-oncogene c-kit blocks development of interstitial cells and electrical rhythmicity in murine intestine","volume":"480","author":"Ward","year":"1994","journal-title":"J. Physiol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1540\/jsmr.47.111","article-title":"Interstitial cells of Cajal in the gastrointestinal musculature of W(jic) c-kit mutant mice","volume":"47","author":"Iino","year":"2011","journal-title":"J. Smooth Muscle Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"G228","DOI":"10.1152\/ajpgi.00363.2016","article-title":"Conditional genetic deletion of Ano1 in interstitial cells of Cajal impairs Ca2+ transients and slow waves in adult mouse small intestine","volume":"312","author":"Malysz","year":"2017","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"4051","DOI":"10.1113\/jphysiol.2014.277152","article-title":"Ano1, a Ca2+-activated Cl\u2212 channel, coordinates contractility in mouse intestine by Ca2+ transient coordination between interstitial cells of Cajal","volume":"592","author":"Singh","year":"2014","journal-title":"J. Physiol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1731","DOI":"10.2337\/diabetes.49.10.1731","article-title":"Remodeling of networks of interstitial cells of Cajal in a murine model of diabetic gastroparesis","volume":"49","author":"Ordog","year":"2000","journal-title":"Diabetes"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1748","DOI":"10.1053\/j.gastro.2004.09.053","article-title":"Intestinal surgical resection disrupts electrical rhythmicity, neural responses, and interstitial cell networks","volume":"127","author":"Yanagida","year":"2004","journal-title":"Gastroenterology"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1111\/j.1469-7793.2001.0555c.xd","article-title":"Loss of interstitial cells of Cajal and development of electrical dysfunction in murine small bowel obstruction","volume":"536","author":"Chang","year":"2001","journal-title":"J. Physiol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1111\/j.1365-2982.2010.01590.x","article-title":"Changes in interstitial cells of cajal with age in the human stomach and colon","volume":"23","author":"Gibbons","year":"2011","journal-title":"Neurogastroenterol. Motil."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"78226","DOI":"10.18632\/oncotarget.12909","article-title":"Hedgehog pathway dysregulation contributes to the pathogenesis of human gastrointestinal stromal tumors via GLI-mediated activation of KIT expression","volume":"7","author":"Tang","year":"2016","journal-title":"Oncotarget"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"10131","DOI":"10.3748\/wjg.v22.i46.10131","article-title":"Characterization of smooth muscle, enteric nerve, interstitial cells of Cajal, and fibroblast-like cells in the gastric musculature of patients with diabetes mellitus","volume":"22","author":"Park","year":"2016","journal-title":"World J. Gastroenterol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"317","DOI":"10.4196\/kjpp.2010.14.5.317","article-title":"Regional Distribution of Interstitial Cells of Cajal (ICC) in Human Stomach","volume":"14","author":"Yun","year":"2010","journal-title":"Korean J. Physiol. Pharmacol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"6105","DOI":"10.1113\/jphysiol.2011.217497","article-title":"Analysis of pacemaker activity in the human stomach","volume":"589","author":"Rhee","year":"2011","journal-title":"J. Physiol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1852","DOI":"10.1053\/j.gastro.2007.02.049","article-title":"The Mechanism and Spread of Pacemaker Activity Through Myenteric Interstitial Cells of Cajal in Human Small Intestine","volume":"132","author":"Lee","year":"2007","journal-title":"Gastroenterology"},{"key":"ref_60","first-page":"G1111","article-title":"Sodium current in human intestinal interstitial cells of Cajal","volume":"285","author":"Strege","year":"2003","journal-title":"Am. J. Physiol."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Chen, Z.-H., Zhang, Y.-C., Jiang, W.-F., Yang, C., Zou, G.-M., Kong, Y., and Cai, W. (2014). Characterization of Interstitial Cajal Progenitors Cells and Their Changes in Hirschsprung\u2019s Disease. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0086100"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1111\/j.1365-2982.2011.01729.x","article-title":"Immunoreactivity for Ano1 detects depletion of Kit-positive interstitial cells of Cajal in patients with slow transit constipation","volume":"23","author":"Kashyap","year":"2011","journal-title":"Neurogastroenterol. Motil."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1575","DOI":"10.1053\/j.gastro.2011.01.046","article-title":"Cellular Changes in Diabetic and Idiopathic Gastroparesis","volume":"140","author":"Grover","year":"2011","journal-title":"Gastroenterology"},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Herring, B.P., Chen, M., Mihaylov, P., Hoggatt, A.M., Gupta, A., Nakeeb, A., Choi, J.N., and Wo, J.M. (2019). Transcriptome profiling reveals significant changes in the gastric muscularis externa with obesity that partially overlap those that occur with idiopathic gastroparesis. BMC Med Genom., 12.","DOI":"10.1186\/s12920-019-0550-3"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Wang, Q., Wang, K., Solorzano-Vargas, R.S., Lin, P.Y., Walthers, C.M., Thomas, A.L., Mart\u00edn, M.G., and Dunn, J.C.Y. (2018). Bioengineered intestinal muscularis complexes with long-term spontaneous and periodic contractions. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0195315"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"13544","DOI":"10.1038\/s41598-018-31992-4","article-title":"Bioengineering functional smooth muscle with spontaneous rhythmic contraction in vitro","volume":"8","author":"Kobayashi","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"e86492","DOI":"10.1172\/jci.insight.86492","article-title":"A xenogeneic-free system generating functional human gut organoids from pluripotent stem cells","volume":"2","author":"Uchida","year":"2017","journal-title":"JCI Insight"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1038\/nm.4233","article-title":"Engineered human pluripotent-stem-cell-derived intestinal tissues with a functional enteric nervous system","volume":"23","author":"Workman","year":"2017","journal-title":"Nat. Med."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"251","DOI":"10.2174\/1574888X09666141112120040","article-title":"Is there a role for human pluripotent stem cells in modelling interstitial cells of Cajal and gut motility disorders?","volume":"10","author":"Meng","year":"2015","journal-title":"Curr. Stem Cell Res. Ther."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Zhou, J., O\u2019Connor, M.D., and Ho, V. (2017). The Potential for Gut Organoid Derived Interstitial Cells of Cajal in Replacement Therapy. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18102059"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1038\/s41598-018-36607-6","article-title":"Smooth Muscle Transcriptome Browser: Offering genome-wide references and expression profiles of transcripts expressed in intestinal SMC, ICC, and PDGFR\u03b1+ cells","volume":"9","author":"Breland","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1111\/bph.14459","article-title":"Nitric oxide and its role as a non-adrenergic, non-cholinergic inhibitory neurotransmitter in the gastrointestinal tract","volume":"176","author":"Sanders","year":"2019","journal-title":"Br. J. Pharm."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1573","DOI":"10.1111\/j.1582-4934.2011.01451.x","article-title":"Ultrastructural differences between diabetic and idiopathic gastroparesis","volume":"16","author":"Grover","year":"2012","journal-title":"J. Cell. Mol. Med."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1016\/S0016-5085(96)70057-4","article-title":"Interstitial cells of Cajal in human colon and in Hirschsprung\u2019s disease","volume":"111","author":"Vanderwinden","year":"1996","journal-title":"Gastroenterology"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"928","DOI":"10.5858\/2002-126-0928-ADOICO","article-title":"Altered Distribution of Interstitial Cells of Cajal in Hirschsprung Disease","volume":"126","author":"Rolle","year":"2002","journal-title":"Arch. Pathol. Lab. Med."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1136\/gut.51.4.496","article-title":"Pan-colonic decrease in interstitial cells of Cajal in patients with slow transit constipation","volume":"51","author":"Lyford","year":"2002","journal-title":"Gut"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1459","DOI":"10.1053\/gast.2002.36600","article-title":"Enteric nerves and interstitial cells of Cajal are altered in patients with slow-transit constipation and megacolon","volume":"123","author":"Wedel","year":"2002","journal-title":"Gastroenterology"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1097\/MCO.0b013e32830b5d37","article-title":"The clinical significance of gastrointestinal changes with aging","volume":"11","author":"Bhutto","year":"2008","journal-title":"Curr. Opin. Clin. Nutr. Metab. Care"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1159\/000099474","article-title":"Basic mechanisms of the aging gastrointestinal tract","volume":"25","author":"Salles","year":"2007","journal-title":"Dig. Dis."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1097\/MCO.0000000000000238","article-title":"The ageing gastrointestinal tract","volume":"19","author":"Soenen","year":"2016","journal-title":"Curr. Opin. Clin. Nutr. Metab. Care"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"3851","DOI":"10.18632\/aging.101677","article-title":"Aging-dependent decrease in the numbers of enteric neurons, interstitial cells of Cajal and expression of connexin43 in various regions of gastrointestinal tract","volume":"10","author":"Sun","year":"2018","journal-title":"Aging"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"5160","DOI":"10.1111\/jcmm.13794","article-title":"Interstitial cell network volume is reduced in the terminal bowel of ageing mice","volume":"22","author":"Gamage","year":"2018","journal-title":"J. Cell. Mol. Med."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1007\/s11892-014-0527-8","article-title":"Diabetic gastroparesis: Functional\/morphologic background, diagnosis, and treatment options","volume":"14","author":"Horvath","year":"2014","journal-title":"Curr. Diabetes Rep."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1111\/j.1365-2265.2008.03351.x","article-title":"Relationship between clinical features and gastric emptying disturbances in diabetes mellitus","volume":"70","author":"Bharucha","year":"2009","journal-title":"Clin. Endocrinol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1016\/j.cgh.2014.06.034","article-title":"Relationship between glycemic control and gastric emptying in poorly controlled type 2 diabetes","volume":"13","author":"Bharucha","year":"2015","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"486","DOI":"10.5056\/jnm15075","article-title":"Is Interstitial Cells of Cajal\u2013opathy Present in Gastroparesis?","volume":"21","author":"Bashashati","year":"2015","journal-title":"J. Neurogastroenterol. Motil."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1275","DOI":"10.1111\/nmo.12389","article-title":"Association of low numbers of CD206-positive cells with loss of ICC in the gastric body of patients with diabetic gastroparesis","volume":"26","author":"Bernard","year":"2014","journal-title":"Neurogastroenterol. Motil."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1186\/s12920-018-0379-1","article-title":"Transcriptomic signatures reveal immune dysregulation in human diabetic and idiopathic gastroparesis","volume":"11","author":"Grover","year":"2018","journal-title":"BMC Med. Genom."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"G716","DOI":"10.1152\/ajpgi.00115.2019","article-title":"Proteomics in gastroparesis: Unique and overlapping protein signatures in diabetic and idiopathic gastroparesis","volume":"317","author":"Grover","year":"2019","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1111\/j.1440-1746.2008.05326.x","article-title":"Disturbed gastrointestinal motility and decreased interstitial cells of Cajal in diabetic db\/db mice","volume":"23","author":"Yamamoto","year":"2008","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"2055","DOI":"10.1053\/j.gastro.2008.09.003","article-title":"Heme oxygenase-1 protects interstitial cells of Cajal from oxidative stress and reverses diabetic gastroparesis","volume":"135","author":"Choi","year":"2008","journal-title":"Gastroenterology"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1016\/j.jcmgh.2016.04.006","article-title":"Interleukin 10 Restores Gastric Emptying, Electrical Activity, and Interstitial Cells of Cajal Networks in Diabetic Mice","volume":"2","author":"Choi","year":"2016","journal-title":"Cell. Mol. Gastroenterol. Hepatol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1053\/j.gastro.2005.12.027","article-title":"Reduced stem cell factor links smooth myopathy and loss of interstitial cells of cajal in murine diabetic gastroparesis","volume":"130","author":"Horvath","year":"2006","journal-title":"Gastroenterology"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1053\/j.gastro.2017.04.020","article-title":"Hyperglycemia Increases Interstitial Cells of Cajal via MAPK1 and MAPK3 Signaling to ETV1 and KIT, Leading to Rapid Gastric Emptying","volume":"153","author":"Hayashi","year":"2017","journal-title":"Gastroenterology"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1007\/s00383-015-3822-9","article-title":"Use of anoctamin 1 (ANO1) to evaluate interstitial cells of Cajal in Hirschsprung\u2019s disease","volume":"32","author":"Coyle","year":"2016","journal-title":"Pediatr. Surg. Int."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1038\/nrc3143","article-title":"Gastrointestinal stromal tumours: Origin and molecular oncology","volume":"11","author":"Corless","year":"2011","journal-title":"Nat. Rev. Cancer"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1016\/S0002-9440(10)64984-X","article-title":"Gastrointestinal stromal tumors may originate from a subset of CD34-positive interstitial cells of Cajal","volume":"156","author":"Robinson","year":"2000","journal-title":"Am. J. Pathol."},{"key":"ref_98","first-page":"728","article-title":"CD117: A sensitive marker for gastrointestinal stromal tumors that is more specific than CD34","volume":"11","author":"Kovatich","year":"1998","journal-title":"Mod. Pathol."},{"key":"ref_99","first-page":"59","article-title":"CD34+ cells in human intestine are fibroblasts adjacent to, but distinct from, interstitial cells of Cajal","volume":"79","author":"Vanderwinden","year":"1999","journal-title":"Lab. Investig. J. Tech. Methods Pathol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1007\/s004410000264","article-title":"CD34 immunoreactivity and interstitial cells of Cajal in the human and mouse gastrointestinal tract","volume":"302","author":"Vanderwinden","year":"2000","journal-title":"Cell Tissue Res."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1002\/path.2296","article-title":"A mouse model of a human multiple GIST family with KIT-Asp820Tyr mutation generated by a knock-in strategy","volume":"214","author":"Nakai","year":"2008","journal-title":"J. Pathol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"6631","DOI":"10.1158\/0008-5472.CAN-05-0891","article-title":"A knock-in mouse model of gastrointestinal stromal tumor harboring kit K641E","volume":"65","author":"Rubin","year":"2005","journal-title":"Cancer Res."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1053\/j.gastro.2010.05.083","article-title":"Kitlow stem cells cause resistance to Kit\/platelet-derived growth factor alpha inhibitors in murine gastrointestinal stromal tumors","volume":"139","author":"Bardsley","year":"2010","journal-title":"Gastroenterology"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"e418","DOI":"10.1111\/nmo.12140","article-title":"Establishment of pacemaker activity in tissues allotransplanted with interstitial cells of Cajal","volume":"25","author":"McCann","year":"2013","journal-title":"Neurogastroenterol. Motil."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/nature00870","article-title":"Pluripotency of mesenchymal stem cells derived from adult marrow","volume":"418","author":"Jiang","year":"2002","journal-title":"Nature"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"2182","DOI":"10.1007\/s10620-009-0991-1","article-title":"Long-term repopulation effects of donor BMDCs on intestinal epithelium","volume":"55","author":"Liu","year":"2010","journal-title":"Dig. Dis. Sci."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"164986","DOI":"10.1155\/2010\/164986","article-title":"Bone marrow derivation of interstitial cells of cajal in small intestine following intestinal injury","volume":"2010","author":"Liu","year":"2010","journal-title":"J. Biomed. Biotechnol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1007\/s00535-009-0077-z","article-title":"Restoration of gut motility in Kit-deficient mice by bone marrow transplantation","volume":"44","author":"Ishii","year":"2009","journal-title":"J. Gastroenterol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"326","DOI":"10.5056\/jnm14026","article-title":"Bone Marrow Derived Kit-positive Cells Colonize the Gut but Fail to Restore Pacemaker Function in Intestines Lacking Interstitial Cells of Cajal","volume":"20","author":"McCann","year":"2014","journal-title":"J. Neurogastroenterol. Motil."},{"key":"ref_110","doi-asserted-by":"crossref","unstructured":"Joddar, B., Tasnim, N., Thakur, V., Kumar, A., McCallum, R.W., and Chattopadhyay, M. (2018). Delivery of Mesenchymal Stem Cells from Gelatin-Alginate Hydrogels to Stomach Lumen for Treatment of Gastroparesis. Bioengineering, 5.","DOI":"10.20944\/preprints201801.0033.v1"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1038\/ng.3487","article-title":"A predictive computational framework for direct reprogramming between human cell types","volume":"48","author":"Rackham","year":"2016","journal-title":"Nat. Genet."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/12\/4540\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:43:02Z","timestamp":1760175782000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/12\/4540"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,6,25]]},"references-count":111,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2020,6]]}},"alternative-id":["ijms21124540"],"URL":"https:\/\/doi.org\/10.3390\/ijms21124540","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,6,25]]}}}