{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T20:14:40Z","timestamp":1793304880431,"version":"4.5.0"},"reference-count":96,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2023,2,3]],"date-time":"2023-02-03T00:00:00Z","timestamp":1675382400000},"content-version":"vor","delay-in-days":2,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82201915"],"award-info":[{"award-number":["82201915"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp; Translational Med"],"published-print":{"date-parts":[[2023,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Hirschsprung's disease (HSCR) is a relatively common congenital disability. Accumulating extracellular matrix (ECM) prompts intestinal fibrosis remodelling in the aganglionic segments of HSCR. The contributions of various cellular subsets in the fibrogenesis of HSCR segments are poorly understood.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Single\u2010cell transcriptomics from 8 aganglionic segments and 5 normal segments of 7 HSCR subjects and 26 healthy segments of seven healthy donors were analysed. Fibrotic phenotype and alterations were explored using differential expression analysis and single\u2010cell trajectory analysis. Fibrosis\u2010related transcription factors were inferred through single\u2010cell regulatory network inference. Bulk transcriptomic data, proteomic data, immunohistochemistry (IHC) and real\u2010time polymerase chain reaction were used to validate the alterations in the HSCR intestine.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Various collagen, fibronectin and laminin protein\u2010coding genes expression were up\u2010regulated in the stromal and glial cells of the HSCR intestine. The number of fibroblasts and myofibroblasts in the aganglionic segments increased, and more myofibroblasts were activated at an earlier stage in HSCR segments, which infers that there is an intestinal fibrosis phenotype in HSCR segments. The fibrotic regulators <jats:italic>POSTN<\/jats:italic>, <jats:italic>ANXA1<\/jats:italic> and <jats:italic>HSP70<\/jats:italic> were highly expressed in the ECM\u2010related cellular subsets in the transitional segments and aganglionic segments. The transcription factor regulatory network revealed that fibrosis\u2010related and megacolon\u2010related <jats:italic>NR2F1<\/jats:italic> in the fibroblasts and glial subsets was up\u2010regulated in the aganglionic segment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This work identifies intestinal fibrosis and related regulators in aganglionic segments of HSCR; hence, anti\u2010fibrotic therapy may be considered to prevent HSCR\u2010associated enterocolitis (HAEC), relieve intestinal stricture and improve cell therapy.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.1193","type":"journal-article","created":{"date-parts":[[2023,2,4]],"date-time":"2023-02-04T06:32:45Z","timestamp":1675492365000},"source":"Crossref","is-referenced-by-count":29,"title":["Intestinal fibrosis in aganglionic segment of Hirschsprung's disease revealed by single\u2010cell RNA sequencing"],"prefix":"10.1002","volume":"13","author":[{"given":"Shiwei","family":"He","sequence":"first","affiliation":[{"name":"Department of Pediatric Surgery Shanghai Key Laboratory of Birth Defect Children's Hospital of Fudan University Ministry of Health  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junfeng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery Shanghai Key Laboratory of Birth Defect Children's Hospital of Fudan University Ministry of Health  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanlei","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery Shanghai Key Laboratory of Birth Defect Children's Hospital of Fudan University Ministry of Health  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fanyang","family":"Kong","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery Shanghai Key Laboratory of Birth Defect Children's Hospital of Fudan University Ministry of Health  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ran","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery Shanghai Key Laboratory of Birth Defect Children's Hospital of Fudan University Ministry of Health  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Zhan","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery Shanghai Key Laboratory of Birth Defect Children's Hospital of Fudan University Ministry of Health  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zifeng","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery Shanghai Key Laboratory of Birth Defect Children's Hospital of Fudan University Ministry of Health  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunjing","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery Shanghai Key Laboratory of Birth Defect Children's Hospital of Fudan University Ministry of Health  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingdu","family":"Meng","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery Shanghai Key Laboratory of Birth Defect Children's Hospital of Fudan University Ministry of Health  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yankang","family":"Ren","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery Shanghai Key Laboratory of Birth Defect Children's Hospital of Fudan University Ministry of Health  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery Shanghai Key Laboratory of Birth Defect Children's Hospital of Fudan University Ministry of Health  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gong","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery Shanghai Key Laboratory of Birth Defect Children's Hospital of Fudan University Ministry of Health  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery Shanghai Key Laboratory of Birth Defect Children's Hospital of Fudan University Ministry of Health  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Song","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery Shanghai Key Laboratory of Birth Defect Children's Hospital of Fudan University Ministry of Health  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9712-4573","authenticated-orcid":false,"given":"Shan","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery Shanghai Key Laboratory of Birth Defect Children's Hospital of Fudan University Ministry of Health  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9645-4768","authenticated-orcid":false,"given":"Rui","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery Shanghai Key Laboratory of Birth Defect Children's Hospital of Fudan University Ministry of Health  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,2,3]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrgastro.2017.149"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-030-15647-3"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00383\u2010017\u20104065\u20108"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3904"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00383\u2010017\u20104181\u20105"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.128132"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl\u20102014\u2010308048"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1097\/mpg.0000000000002627"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1055\/s\u20100032\u20101322544"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/0016-5085(92)90761-M"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/0012\u20101606(88)90217\u20105"},{"issue":"2","key":"e_1_2_8_13_1","first-page":"113","article-title":"Immunohistochemical study of miroenvironmental changes in intestinal wall of Hirschsprung's disease","volume":"24","author":"Zhao Y","year":"2003","journal-title":"Chinese Journal of Pediatric Surgery"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci83178"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2022.02.094"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2017.11.184"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/nmo.13134"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/0022\u20103468(94)90101\u20105"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/0022\u20103468(92)90545\u2010i"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12519\u2010008\u20100027\u20105"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.160317"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0022\u20103468(85)80209\u20108"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10571\u2010019\u201000759\u20104"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00383\u2010017\u20104180\u20106"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1136\/gut.2010.235614"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mam.2018.10.003"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2021.105444"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2020.117470"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1093\/ibd\/izaa015"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.11747"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1401779"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00051.2005"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2016.09.047"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis\u20102018\u2010214865"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2022.02.077"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078\u20100432.Ccr\u201019\u20100187"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13578\u2010019\u20100284\u20100"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/modpathol.2011.99"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.091751"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.06.024"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.227900"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1097\/MNH.0b013e328344c3d4"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.12.9.2730"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010020\u20102941\u20101"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1159\/000485325"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010021\u201085096\u20107"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010021\u201024110\u2010y"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.722170"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1111\/apha.12586"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.3349\/ymj.2015.56.6.1619"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.1155\/2013\/621538"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2012.10.001"},{"key":"e_1_2_8_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.scitotenv.2020.141531"},{"key":"e_1_2_8_54_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14122962"},{"key":"e_1_2_8_55_1","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.026773"},{"key":"e_1_2_8_56_1","doi-asserted-by":"publisher","DOI":"10.3390\/genes12071037"},{"key":"e_1_2_8_57_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008\u20105472.Can\u201019\u20102373"},{"key":"e_1_2_8_58_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep46565"},{"key":"e_1_2_8_59_1","doi-asserted-by":"publisher","DOI":"10.1111\/1751\u20102980.12883"},{"key":"e_1_2_8_60_1","doi-asserted-by":"publisher","DOI":"10.1007\/978\u2010981\u201013\u20106657\u20104_10"},{"key":"e_1_2_8_61_1","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl\u20102012\u2010304353"},{"key":"e_1_2_8_62_1","doi-asserted-by":"publisher","DOI":"10.1097\/mib.0000000000000512"},{"key":"e_1_2_8_63_1","doi-asserted-by":"publisher","DOI":"10.1042\/cs20211122"},{"key":"e_1_2_8_64_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2020.591561"},{"key":"e_1_2_8_65_1","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2017\u20100268OC"},{"key":"e_1_2_8_66_1","doi-asserted-by":"publisher","DOI":"10.17219\/acem\/44144"},{"key":"e_1_2_8_67_1","doi-asserted-by":"publisher","DOI":"10.1177\/147323000403200206"},{"key":"e_1_2_8_68_1","doi-asserted-by":"publisher","DOI":"10.1089\/scd.2008.0362"},{"key":"e_1_2_8_69_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddq357"},{"key":"e_1_2_8_70_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2013.02.007"},{"key":"e_1_2_8_71_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.crohns.2014.09.008"},{"key":"e_1_2_8_72_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2017.06.013"},{"key":"e_1_2_8_73_1","doi-asserted-by":"publisher","DOI":"10.1111\/sji.12990"},{"issue":"6","key":"e_1_2_8_74_1","first-page":"401","article-title":"Diagnosis and treatment of Hirschsprung's disease: challenges and opportunities","volume":"39","author":"Gao Y","year":"2018","journal-title":"Chinese J Pediatr Surg"},{"issue":"4","key":"e_1_2_8_75_1","first-page":"247","article-title":"Guideline for laparoscopic pull\u2010through for Hirschsprung's disease (2017 edition)","volume":"38","author":"Section of L","year":"2017","journal-title":"Chinese J Pediatr Surg"},{"key":"e_1_2_8_76_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2021.04.003"},{"key":"e_1_2_8_77_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41590\u2010020\u20100743\u20100"},{"key":"e_1_2_8_78_1","doi-asserted-by":"publisher","DOI":"10.3390\/v13112212"},{"key":"e_1_2_8_79_1","doi-asserted-by":"publisher","DOI":"10.2337\/db16\u20100405"},{"key":"e_1_2_8_80_1","doi-asserted-by":"publisher","DOI":"10.1136\/jitc\u20102020\u2010001066"},{"key":"e_1_2_8_81_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010021\u201003852\u20101"},{"key":"e_1_2_8_82_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.matbio.2015.06.003"},{"key":"e_1_2_8_83_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa1043"},{"key":"e_1_2_8_84_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2020.12.456"},{"key":"e_1_2_8_85_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13059\u2010020\u201002210\u20100"},{"key":"e_1_2_8_86_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41587\u2010020\u20100469\u20104"},{"key":"e_1_2_8_87_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13059\u2010021\u201002552\u20103"},{"key":"e_1_2_8_88_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.04.048"},{"key":"e_1_2_8_89_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13059\u2010021\u201002584\u20109"},{"key":"e_1_2_8_90_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2020.11.010"},{"key":"e_1_2_8_91_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cels.2018.11.005"},{"key":"e_1_2_8_92_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.12.016"},{"key":"e_1_2_8_93_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41592\u2010019\u20100619\u20100"},{"key":"e_1_2_8_94_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4463"},{"key":"e_1_2_8_95_1","doi-asserted-by":"publisher","DOI":"10.1089\/omi.2011.0118"},{"key":"e_1_2_8_96_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.2859"},{"key":"e_1_2_8_97_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41596\u2010020\u20100336\u20102"}],"container-title":["Clinical and Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ctm2.1193","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ctm2.1193","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ctm2.1193","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,19]],"date-time":"2023-08-19T04:03:07Z","timestamp":1692417787000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ctm2.1193"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2]]},"references-count":96,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2023,2]]}},"alternative-id":["10.1002\/ctm2.1193"],"URL":"https:\/\/doi.org\/10.1002\/ctm2.1193","archive":["Portico"],"relation":{},"ISSN":["2001-1326","2001-1326"],"issn-type":[{"value":"2001-1326","type":"print"},{"value":"2001-1326","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2]]},"article-number":"e1193"}}