{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:05:23Z","timestamp":1792789523418,"version":"4.5.0"},"reference-count":53,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2020,7,31]],"date-time":"2020-07-31T00:00:00Z","timestamp":1596153600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["NE425\/4-4"],"award-info":[{"award-number":["NE425\/4-4"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"name":"University Leipzig","award":["Open Access Publishing"],"award-info":[{"award-number":["Open Access Publishing"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Bladder dysfunction is characterized by urgency, frequency (pollakisuria, nocturia), and dysuria and may lead to urinary incontinence. Most of these symptoms can be attributed to disturbed bladder sensitivity. There is growing evidence that, besides the urothelium, suburothelial interstitial cells (suICs) are involved in bladder afferent signal processing. The massive expansion of the bladder during the filling phase implicates mechanical stress delivered to the whole bladder wall. Little is known about the reaction of suICs upon mechanical stress. Therefore, we investigated the effects of mechanical stimulation in cultured human suICs. We used fura-2 calcium imaging as a major physiological readout. We found spontaneous intracellular calcium activity in 75 % of the cultured suICs. Defined local pressure application via a glass micropipette led to local increased calcium activity in all stimulated suICs, spreading over the whole cell. A total of 51% of the neighboring cells in a radius of up to 100 \u00b5m from the stimulated cell showed an increased activity. Hypotonic ringer and shear stress also induced calcium transients. We found an 18-times increase in syncytial activity compared to unstimulated controls, resulting in an amplification of the primary calcium signal elicited in single cells by 50%. Our results speak in favor of a high sensitivity of suICs for mechanical stress and support the view of a functional syncytium between suICs, which can amplify and distribute local stimuli. Previous studies of connexin expression in the human bladder suggest that this mechanism could also be relevant in normal and pathological function of the bladder in vivo.<\/jats:p>","DOI":"10.3390\/ijms21155474","type":"journal-article","created":{"date-parts":[[2020,8,3]],"date-time":"2020-08-03T06:16:47Z","timestamp":1596435407000},"page":"5474","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Mechanosensitivity Is a Characteristic Feature of Cultured Suburothelial Interstitial Cells of the Human Bladder"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2484-6994","authenticated-orcid":false,"given":"Jochen","family":"Neuhaus","sequence":"first","affiliation":[{"name":"Department of Urology, Research Laboratory, University of Leipzig, Liebigstr. 19, 04103 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Gonsior","sequence":"additional","affiliation":[{"name":"Department of Urology, University Hospital Leipzig, Liebigstr. 20, 04103 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheng","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Urology, Research Laboratory, University of Leipzig, Liebigstr. 19, 04103 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens-Uwe","family":"Stolzenburg","sequence":"additional","affiliation":[{"name":"Department of Urology, University Hospital Leipzig, Liebigstr. 20, 04103 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank Peter","family":"Berger","sequence":"additional","affiliation":[{"name":"Department of Urology, University Hospital Jena, Am Klinikum 1, 07747 Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,7,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/978-3-642-56879-4_1","article-title":"Structure and function of the bladder neck","volume":"159","author":"Dorschner","year":"2001","journal-title":"Adv. Anat. Embryol. Cell. Biol."},{"key":"ref_2","first-page":"327","article-title":"Neural control of the lower urinary tract","volume":"5","author":"Griffiths","year":"2015","journal-title":"Compr. Physiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"F1084","DOI":"10.1152\/ajprenal.00118.2004","article-title":"Alterations in P2X and P2Y purinergic receptor expression in urinary bladder from normal cats and cats with interstitial cystitis","volume":"287","author":"Birder","year":"2004","journal-title":"Am. J. Physiol. Renal. Physiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1038\/nrurol.2016.13","article-title":"Receptors, channels, and signalling in the urothelial sensory system in the bladder","volume":"13","author":"Merrill","year":"2016","journal-title":"Nat. Rev. Urol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1002\/nau.22465","article-title":"Lamina propria: The functional center of the bladder","volume":"33","author":"Andersson","year":"2014","journal-title":"Neurourol. Urodyn."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1002\/nau.20511","article-title":"On the origin of bladder sensing: Tr(i)ps in urology","volume":"27","author":"Everaerts","year":"2008","journal-title":"Neurourol. Urodyn."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1007\/s00418-018-1655-z","article-title":"Comparative immunohistochemical characterization of interstitial cells in the urinary bladder of human, guinea pig and pig","volume":"149","author":"Steiner","year":"2018","journal-title":"Histochem. Cell Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1555","DOI":"10.1016\/j.juro.2014.05.096","article-title":"Identification of Different Phenotypes of Interstitial Cells in the Upper and Deep Lamina Propria of the Human Bladder Dome","volume":"192","author":"Gevaert","year":"2014","journal-title":"J. Urol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1007\/s00441-017-2694-9","article-title":"Comparative study of the organisation and phenotypes of bladder interstitial cells in human, mouse and rat","volume":"370","author":"Gevaert","year":"2017","journal-title":"Cell Tissue Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1206","DOI":"10.1111\/jcmm.13054","article-title":"The stem cell growth factor receptor KIT is not expressed on interstitial cells in bladder","volume":"21","author":"Gevaert","year":"2017","journal-title":"J. Cell. Mol. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2139","DOI":"10.3892\/etm.2016.3246","article-title":"Structural and functional changes in gap junctional intercellular communication in a rat model of overactive bladder syndrome induced by partial bladder outlet obstruction","volume":"11","author":"Zhou","year":"2016","journal-title":"Exp. Ther. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"F46","DOI":"10.1152\/ajprenal.90207.2008","article-title":"Basic fibroblast growth factor causes urinary bladder overactivity through gap junction generation in the smooth muscle","volume":"297","author":"Imamura","year":"2009","journal-title":"Am. J. Physiol. Renal. Physiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1007\/s00345-008-0365-x","article-title":"Connexin45 expression in the human obstructed detrusor muscle","volume":"27","author":"John","year":"2009","journal-title":"World J. Urol."},{"key":"ref_14","first-page":"475.e1\u2013e7","article-title":"Therapeutic effects of connexin inhibitors on detrusor overactivity induced by bladder outlet obstruction in rats","volume":"78","author":"Kim","year":"2011","journal-title":"Urology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1007\/s11255-008-9516-7","article-title":"Changes of bladder activity and connexin 43-derived gap junctions after partial bladder-outlet obstruction in rats","volume":"41","author":"Miyazato","year":"2009","journal-title":"Int. Urol. Nephrol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.1016\/j.urology.2005.01.043","article-title":"Decreased cellular membrane expression of gap junctional protein, connexin 43, in rat detrusor muscle with chronic partial bladder outlet obstruction","volume":"65","author":"Mori","year":"2005","journal-title":"Urology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1819","DOI":"10.1002\/jcp.24333","article-title":"Myocardin and microRNA-1 modulate bladder activity through connexin 43 expression during post-natal development","volume":"228","author":"Imamura","year":"2013","journal-title":"J. Cell. Physiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1440","DOI":"10.1016\/j.eururo.2008.11.009","article-title":"Suburothelial Myofibroblasts in the Human Overactive Bladder and the Effect of Botulinum Neurotoxin Type A Treatment","volume":"55","author":"Roosen","year":"2009","journal-title":"Eur. Urol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1111\/j.1464-410X.2005.05703.x","article-title":"Alterations in connexin expression in the bladder of patients with urge symptoms","volume":"96","author":"Neuhaus","year":"2005","journal-title":"BJU Int."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2502","DOI":"10.1002\/nau.23767","article-title":"TGF-\u03b21 and connexin-43 expression in neurogenic bladder from rats with sacral spinal cord injury","volume":"37","author":"Zhao","year":"2018","journal-title":"Neurourol. Urodyn."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Heinrich, M., Oberbach, A., Schlichting, N., Stolzenburg, J.-U., and Neuhaus, J. (2011). Cytokine Effects on Gap Junction Communication and Connexin Expression in Human Bladder Smooth Muscle Cells and Suburothelial Myofibroblasts. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0020792"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1016\/j.eururo.2008.03.090","article-title":"TGF-beta1 inhibits Cx43 expression and formation of functional syncytia in cultured smooth muscle cells from human detrusor","volume":"55","author":"Neuhaus","year":"2009","journal-title":"Eur. Urol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"63","DOI":"10.3389\/fphys.2014.00063","article-title":"The role of pannexin hemichannels in inflammation and regeneration","volume":"5","author":"Makarenkova","year":"2014","journal-title":"Front. Physiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2152","DOI":"10.1038\/srep02152","article-title":"Pannexin 1 involvement in bladder dysfunction in a multiple sclerosis model","volume":"3","author":"Negoro","year":"2013","journal-title":"Sci. Rep."},{"key":"ref_25","unstructured":"Van Rossum, G., and Drake, F.L. (1995). Python 3 Reference Manual, CreateSpace."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2000","DOI":"10.1111\/jcmm.12375","article-title":"Telocytes subtypes in human urinary bladder","volume":"18","author":"Vannucchi","year":"2014","journal-title":"J. Cell. Mol. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1288","DOI":"10.1016\/j.juro.2009.12.060","article-title":"Bladder afferent signaling: Recent findings","volume":"183","author":"Kanai","year":"2010","journal-title":"J. Urol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1002\/nau.20483","article-title":"The function of suburothelial myofibroblasts in the bladder","volume":"26","author":"Fry","year":"2007","journal-title":"Neurourol. Urodyn."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1152\/ajprenal.00133.2008","article-title":"Modulation of bladder myofibroblast activity: Implications for bladder function","volume":"295","author":"Sui","year":"2008","journal-title":"Am. J. Physiol. Renal. Physiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"966","DOI":"10.1002\/nau.23099","article-title":"Urothelial ATP signaling: What is its role in bladder sensation","volume":"36","author":"Takezawa","year":"2017","journal-title":"Neurourol. Urodyn."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1152\/physrev.00030.2012","article-title":"Urothelial signaling","volume":"93","author":"Birder","year":"2013","journal-title":"Physiol. Rev."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"87","DOI":"10.3389\/fnsys.2017.00087","article-title":"Rhythmic Calcium Events in the Lamina Propria Network of the Urinary Bladder of Rat Pups","volume":"11","author":"Heppner","year":"2017","journal-title":"Front. Syst. Neurosci."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Cheng, S., Scigalla, F.P., Speroni di Fenizio, P., Zhang, Z.G., Stolzenburg, J.U., and Neuhaus, J. (2011). ATP enhances spontaneous calcium activity in cultured suburothelial myofibroblasts of the human bladder. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0025769"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"F1018","DOI":"10.1152\/ajprenal.00183.2007","article-title":"The Role of Gap Junctions in Spontaneous Activity of the Rat Bladder","volume":"293","author":"Ikeda","year":"2007","journal-title":"Am. J. Physiol. Renal. Physiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1097\/01.ju.0000108120.28291.eb","article-title":"Electrical characteristics of suburothelial cells isolated from the human bladder","volume":"171","author":"Sui","year":"2004","journal-title":"J. Urol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1515\/BMC.2011.039","article-title":"Telocytes","volume":"2","author":"Popescu","year":"2011","journal-title":"Biomol. Concepts."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2085","DOI":"10.1111\/j.1582-4934.2011.01504.x","article-title":"Identification of telocytes in the upper lamina propria of the human urinary tract","volume":"16","author":"Gevaert","year":"2012","journal-title":"J. Cell. Mol. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1007\/s00120-007-1480-9","article-title":"Structure and function of suburothelial myofibroblasts in the human urinary bladder under normal and pathological conditions","volume":"46","author":"Neuhaus","year":"2007","journal-title":"Urol. A"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1812","DOI":"10.1126\/science.1465619","article-title":"Range of messenger action of calcium ion and inositol 1,4,5-trisphosphate","volume":"258","author":"Allbritton","year":"1992","journal-title":"Science"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2708","DOI":"10.1073\/pnas.86.8.2708","article-title":"Hepatocyte gap junctions are permeable to the second messenger, inositol 1,4,5-trisphosphate, and to calcium ions","volume":"86","author":"Connor","year":"1989","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"277","DOI":"10.3109\/15419060109080737","article-title":"Calmodulin colocalizes with connexins and plays a direct role in gap junction channel gating","volume":"8","author":"Sotkis","year":"2001","journal-title":"Cell. Commun. Adhes."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.bbamem.2003.10.020","article-title":"Chemical gating of gap junction channels","volume":"1662","author":"Peracchia","year":"2004","journal-title":"Biochim. Biophys. Acta (BBA) Biomembr."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"F1065","DOI":"10.1152\/ajprenal.00229.2006","article-title":"Origin of spontaneous activity in neonatal and adult rat bladders and its enhancement by stretch and muscarinic agonists","volume":"292","author":"Kanai","year":"2007","journal-title":"Am. J. Physiol. Renal. Physiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"H1339","DOI":"10.1152\/ajpheart.01021.2013","article-title":"Effects of methylglyoxal on human cardiac fibroblast: Roles of transient receptor potential ankyrin 1 (TRPA1) channels","volume":"307","author":"Oguri","year":"2014","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_45","first-page":"a004549","article-title":"Calcium signaling in smooth muscle","volume":"3","author":"Werner","year":"2011","journal-title":"Cold Spring Harb. Perspect Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1002\/jcp.1041610202","article-title":"Slow oscillations of free intracellular calcium ion concentration in human fibroblasts responding to mechanical stretch","volume":"161","author":"Arora","year":"1994","journal-title":"J. Cell. Physiol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.cophys.2017.10.003","article-title":"The ryanodine receptor: Advances in structure and organization","volume":"1","author":"Williams","year":"2018","journal-title":"Curr. Opin. Physiol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"H2190","DOI":"10.1152\/ajpheart.01146.2011","article-title":"Inositol trisphosphate receptors in smooth muscle cells","volume":"302","author":"Narayanan","year":"2012","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"27","DOI":"10.3389\/fphar.2011.00027","article-title":"Porcine Bladder Urothelial, Myofibroblast, and Detrusor Muscle Cells: Characterization and ATP Release","volume":"2","author":"Cheng","year":"2011","journal-title":"Front. Pharmacol."},{"key":"ref_50","unstructured":"WMA (2008). World medical association declaration of helsinki Ethical Principles for Medical Research Involving Human Subjects. Bull. World Health Organ., 79, 373."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1007\/BF00595685","article-title":"Action potential and net membrane currents of isolated smooth muscle cells(urinary bladder of the GP)","volume":"405","author":"Isenberg","year":"1985","journal-title":"Pfl\u00fcgers Arch."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1007\/s00441-002-0559-2","article-title":"Detrusor smooth muscle cells of the guinea-pig are functionally coupled via gap junctions in situ and in cell culture","volume":"309","author":"Neuhaus","year":"2002","journal-title":"Cell. Tissue Res."},{"key":"ref_53","unstructured":"Rasband, W.S., and ImageJ (2020, June 15). US National Institutes of Health, Bethesda, Maryland, USA, 1997\u20132016, Available online: http:\/\/rsb.info.nih.gov\/ij\/."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/15\/5474\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:53:14Z","timestamp":1760176394000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/15\/5474"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,7,31]]},"references-count":53,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2020,8]]}},"alternative-id":["ijms21155474"],"URL":"https:\/\/doi.org\/10.3390\/ijms21155474","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,7,31]]}}}