{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T22:02:15Z","timestamp":1791928935130,"version":"4.3.4"},"reference-count":50,"publisher":"Association for Research in Vision and Ophthalmology (ARVO)","issue":"1","license":[{"start":{"date-parts":[[2025,1,6]],"date-time":"2025-01-06T00:00:00Z","timestamp":1736121600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Invest. Ophthalmol. Vis. Sci."],"published-print":{"date-parts":[[2025,1,6]]},"DOI":"10.1167\/iovs.66.1.8","type":"journal-article","created":{"date-parts":[[2025,1,6]],"date-time":"2025-01-06T10:30:48Z","timestamp":1736159448000},"page":"8","source":"Crossref","is-referenced-by-count":3,"title":["RSPO3 Promotes Proliferation and Self-Renewal of Limbal Epithelial Stem Cells Through a WNT\/\u03b2-Catenin-Independent Signaling Pathway"],"prefix":"10.1167","volume":"66","author":[{"given":"Yan","family":"Shen","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Eye, Ear, Nose, and Throat Hospital of Fudan University, Shanghai, China"},{"name":"Department of Ophthalmology, Huadong Hospital of Fudan University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiajia","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Eye, Ear, Nose, and Throat Hospital of Fudan University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiqin","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Eye, Ear, Nose, and Throat Hospital of Fudan University, Shanghai, China"},{"name":"Research Centre, Eye, Ear, Nose, and Throat Hospital of Fudan University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xichen","family":"Wan","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Eye, Ear, Nose, and Throat Hospital of Fudan University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Eye, Ear, Nose, and Throat Hospital of Fudan University, Shanghai, China"},{"name":"Research Centre, Eye, Ear, Nose, and Throat Hospital of Fudan University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qihua","family":"Le","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Eye, Ear, Nose, and Throat Hospital of Fudan University, Shanghai, China"},{"name":"Research Centre, Eye, Ear, Nose, and Throat Hospital of Fudan University, Shanghai, China"},{"name":"Key Laboratory of Myopia and Related Eye Diseases, Chinese Academy of Medical Sciences, Eye, Ear, Nose and Throat Hospital of Fudan University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"27","reference":[{"issue":"4","key":"bib1","doi-asserted-by":"publisher","first-page":"1001","DOI":"10.1242\/dev.110.4.1001","article-title":"Stem cells attributes, cycles, spirals, pitfalls and uncertainties. Lessons for and from the crypt","volume":"110","author":"Potten","year":"1990","journal-title":"Development"},{"issue":"1","key":"bib2","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1002\/stem.2191","article-title":"Cell adhesion molecules and stem cell-niche-interactions in the limbal stem cell niche","volume":"34","author":"Polisetti","year":"2016","journal-title":"Stem Cells"},{"issue":"1","key":"bib3","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1083\/jcb.103.1.49","article-title":"Differentiation-related expression of a major 64K corneal keratin in vivo and in culture suggests limbal location of corneal epithelial stem cells","volume":"103","author":"Schermer","year":"1986","journal-title":"J Cell Biol"},{"issue":"3","key":"bib4","doi-asserted-by":"publisher","first-page":"364","DOI":"10.1097\/ICO.0000000000001820","article-title":"Global consensus on definition, classification, diagnosis, and staging of limbal stem cell deficiency","volume":"38","author":"Deng","year":"2019","journal-title":"Cornea"},{"key":"bib5","doi-asserted-by":"publisher","first-page":"9798374","DOI":"10.1155\/2016\/9798374","article-title":"Limbal stem cell deficiency: current treatment options and emerging therapies","volume":"2016","author":"Haagdorens","year":"2016","journal-title":"Stem Cells Int"},{"issue":"10","key":"bib6","doi-asserted-by":"publisher","first-page":"1291","DOI":"10.1097\/ICO.0000000000002358","article-title":"Global consensus on the management of limbal stem cell deficiency","volume":"39","author":"Deng","year":"2020","journal-title":"Cornea"},{"issue":"2","key":"bib7","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1056\/NEJMoa0905955","article-title":"Limbal stem-cell therapy and long-term corneal regeneration","volume":"363","author":"Rama","year":"2010","journal-title":"N Engl J Med"},{"issue":"1","key":"bib8","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s13577-022-00794-2","article-title":"The progress in techniques for culturing human limbal epithelial stem cells","volume":"36","author":"Shen","year":"2023","journal-title":"Hum Cell"},{"issue":"6","key":"bib9","doi-asserted-by":"publisher","first-page":"863","DOI":"10.1002\/cbin.11797","article-title":"Wnt signaling pathway: a comprehensive review","volume":"46","author":"Hayat","year":"2022","journal-title":"Cell Biol Int"},{"issue":"1","key":"bib10","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1167\/iovs.18-25740","article-title":"Wnt signaling is required for the maintenance of human limbal stem\/progenitor cells in vitro","volume":"60","author":"Gonz\u00e1lez","year":"2019","journal-title":"Invest Ophthalmol Vis Sci"},{"issue":"7","key":"bib11","doi-asserted-by":"publisher","first-page":"4734","DOI":"10.1167\/iovs.10-6486","article-title":"Wnt\/beta-catenin signaling regulates proliferation of human cornea epithelial stem\/progenitor cells","volume":"52","author":"Nakatsu","year":"2011","journal-title":"Invest Ophthalmol Vis Sci"},{"issue":"10","key":"bib12","doi-asserted-by":"publisher","first-page":"e13460","DOI":"10.1111\/cpr.13460","article-title":"WNT16b promotes the proliferation and self-renewal of human limbal epithelial stem\/progenitor cells via activating the calcium\/calcineurin A\/NFATC2 pathway","volume":"56","author":"Wan","year":"2023","journal-title":"Cell Prolif"},{"issue":"4","key":"bib13","doi-asserted-by":"publisher","first-page":"864","DOI":"10.1016\/j.stemcr.2022.03.001","article-title":"WNT16B enhances the proliferation and self-renewal of limbal epithelial cells via CXCR4\/MEK\/ERK signaling","volume":"17","author":"Zhao","year":"2022","journal-title":"Stem Cell Reports"},{"issue":"1","key":"bib14","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1016\/j.bbaexp.2003.10.009","article-title":"R-spondin, a novel gene with thrombospondin type 1 domain, was expressed in the dorsal neural tube and affected in Wnts mutants","volume":"1676","author":"Kamata","year":"2004","journal-title":"Biochim Biophys Acta"},{"issue":"3","key":"bib15","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1023\/A:1020479301379","article-title":"Cloning and identification of a cDNA that encodes a novel human protein with thrombospondin type I repeat domain, hPWTSR","volume":"29","author":"Chen","year":"2002","journal-title":"Mol Biol Rep"},{"issue":"4","key":"bib16","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1016\/j.devcel.2004.07.019","article-title":"R-Spondin2 is a secreted activator of Wnt\/beta-catenin signaling and is required for Xenopus myogenesis","volume":"7","author":"Kazanskaya","year":"2004","journal-title":"Dev Cell"},{"issue":"1","key":"bib17","doi-asserted-by":"publisher","first-page":"23","DOI":"10.4161\/cc.5.1.2305","article-title":"R-Spondin proteins: a novel link to beta-catenin activation","volume":"5","author":"Kim","year":"2006","journal-title":"Cell Cycle"},{"issue":"6","key":"bib18","doi-asserted-by":"publisher","first-page":"2588","DOI":"10.1091\/mbc.e08-02-0187","article-title":"R-Spondin family members regulate the Wnt pathway by a common mechanism","volume":"19","author":"Kim","year":"2008","journal-title":"Mol Biol Cell"},{"issue":"3","key":"bib19","doi-asserted-by":"publisher","first-page":"242","DOI":"10.1186\/gb-2012-13-3-242","article-title":"The R-spondin protein family","volume":"13","author":"de Lau","year":"2012","journal-title":"Genome Biol"},{"issue":"7653","key":"bib20","doi-asserted-by":"publisher","first-page":"238","DOI":"10.1038\/nature22313","article-title":"Non-equivalence of Wnt and R-spondin ligands during Lgr5(+) intestinal stem-cell self-renewal","volume":"545","author":"Yan","year":"2017","journal-title":"Nature"},{"issue":"2","key":"bib21","doi-asserted-by":"publisher","first-page":"44","DOI":"10.3390\/biomedicines7020044","article-title":"The role of Wnt and R-spondin in the stomach during health and disease","volume":"7","author":"Fischer","year":"2019","journal-title":"Biomedicines"},{"issue":"20","key":"bib22","doi-asserted-by":"publisher","first-page":"2205","DOI":"10.1101\/gad.245142.114","article-title":"R-spondin1 is a novel hormone mediator for mammary stem cell self-renewal","volume":"28","author":"Cai","year":"2014","journal-title":"Genes Dev"},{"issue":"4","key":"bib23","doi-asserted-by":"publisher","first-page":"101019","DOI":"10.1016\/j.isci.2020.101019","article-title":"Transcriptional profiling of the adult hair follicle mesenchyme reveals R-spondin as a novel regulator of dermal progenitor function","volume":"23","author":"Hagner","year":"2020","journal-title":"iScience"},{"issue":"7","key":"bib24","doi-asserted-by":"publisher","first-page":"1396","DOI":"10.1002\/stem.1390","article-title":"Corneal endothelial cell fate is maintained by LGR5 through the regulation of hedgehog and Wnt pathway","volume":"31","author":"Hirata-Tominaga","year":"2013","journal-title":"Stem Cells"},{"issue":"7264","key":"bib25","doi-asserted-by":"publisher","first-page":"614","DOI":"10.1038\/nature08356","article-title":"Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling","volume":"461","author":"Huang","year":"2009","journal-title":"Nature"},{"issue":"7397","key":"bib26","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1038\/nature11019","article-title":"ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner","volume":"485","author":"Hao","year":"2012","journal-title":"Nature"},{"issue":"12","key":"bib27","doi-asserted-by":"publisher","first-page":"1120","DOI":"10.1038\/embor.2013.167","article-title":"Interaction with both ZNRF3 and LGR4 is required for the signalling activity of R-spondin","volume":"14","author":"Xie","year":"2013","journal-title":"EMBO Rep"},{"issue":"3","key":"bib28","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1016\/j.devcel.2011.01.006","article-title":"Rspo3 binds syndecan 4 and induces Wnt\/PCP signaling via clathrin-mediated endocytosis to promote morphogenesis","volume":"20","author":"Ohkawara","year":"2011","journal-title":"Dev Cell"},{"issue":"1","key":"bib29","doi-asserted-by":"publisher","first-page":"218","DOI":"10.1016\/j.ydbio.2006.08.018","article-title":"R-spondin3 is required for mouse placental development","volume":"301","author":"Aoki","year":"2007","journal-title":"Dev Biol"},{"issue":"22","key":"bib30","doi-asserted-by":"publisher","first-page":"3655","DOI":"10.1242\/dev.027284","article-title":"The Wnt signaling regulator R-spondin 3 promotes angioblast and vascular development","volume":"135","author":"Kazanskaya","year":"2008","journal-title":"Development"},{"key":"bib31","doi-asserted-by":"publisher","first-page":"216301","DOI":"10.1016\/j.canlet.2023.216301","article-title":"R-spondin-3 promotes proliferation and invasion of breast cancer cells independently of Wnt signaling","volume":"568","author":"Ter Steege","year":"2023:","journal-title":"Cancer Lett"},{"issue":"8","key":"bib32","doi-asserted-by":"publisher","first-page":"1246","DOI":"10.1016\/j.stem.2022.06.013","article-title":"Lymphatics and fibroblasts support intestinal stem cells in homeostasis and injury","volume":"29","author":"Goto","year":"2022","journal-title":"Cell Stem Cell"},{"issue":"1","key":"bib33","doi-asserted-by":"publisher","first-page":"4368","DOI":"10.1038\/s41467-019-12349-5","article-title":"R-spondin 3 promotes stem cell recovery and epithelial regeneration in the colon","volume":"10","author":"Harnack","year":"2019","journal-title":"Nat Commun"},{"issue":"4","key":"bib34","doi-asserted-by":"publisher","first-page":"938","DOI":"10.1002\/stem.1582","article-title":"Frizzled 7 maintains the undifferentiated state of human limbal stem\/progenitor cells","volume":"32","author":"Mei","year":"2014","journal-title":"Stem Cells"},{"issue":"10","key":"bib35","doi-asserted-by":"publisher","first-page":"1055","DOI":"10.1038\/embor.2011.175","article-title":"LGR4 and LGR5 are R-spondin receptors mediating Wnt\/beta-catenin and Wnt\/PCP signalling","volume":"12","author":"Glinka","year":"2011","journal-title":"EMBO Rep"},{"issue":"5","key":"bib36","doi-asserted-by":"publisher","first-page":"101075","DOI":"10.1016\/j.isci.2020.101075","article-title":"A small-molecule Wnt mimic improves human limbal stem cell ex vivo expansion","volume":"23","author":"Zhang","year":"2020","journal-title":"iScience"},{"issue":"1","key":"bib37","doi-asserted-by":"publisher","first-page":"11432","DOI":"10.1038\/s41598-022-15263-x","article-title":"Hsa-miR-143-3p inhibits Wnt-\u00df-catenin and MAPK signaling in human corneal epithelial stem cells","volume":"12","author":"Kalaimani","year":"2022","journal-title":"Sci Rep"},{"issue":"7","key":"bib38","doi-asserted-by":"publisher","first-page":"1829","DOI":"10.3390\/biomedicines11071829","article-title":"Wnt\/\u00df-catenin signaling activation induces differentiation in human limbal epithelial stem cells cultured ex vivo","volume":"11","author":"Bisevac","year":"2023","journal-title":"Biomedicines"},{"key":"bib39","first-page":"185:107681","article-title":"Fibronectin regulates the self-renewal of rabbit limbal epithelial stem cells by stimulating the Wnt11\/Fzd7\/ROCK non-canonical Wnt pathway","author":"Zheng","year":"2019","journal-title":"Exp Eye Res"},{"issue":"1","key":"bib40","doi-asserted-by":"publisher","first-page":"20948","DOI":"10.1038\/s41598-021-00273-y","article-title":"Wnt6 plays a complex role in maintaining human limbal stem\/progenitor cells","volume":"11","author":"Bonnet","year":"2021","journal-title":"Sci Rep"},{"key":"bib41","first-page":"303","article-title":"Phospho-regulation of Beta-catenin adhesion and signaling functions","volume":"22","author":"Daugherty","year":"2007","journal-title":"Physiology (Bethesda)"},{"issue":"44","key":"bib42","doi-asserted-by":"publisher","first-page":"36814","DOI":"10.1074\/jbc.M112.356048","article-title":"Wnt5a controls Notch1 signaling through CaMKII-mediated degradation of the SMRT corepressor protein","volume":"287","author":"Ann","year":"2012","journal-title":"J Biol Chem"},{"key":"bib43","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.semcdb.2021.10.004","article-title":"Bridging the gap between non-canonical and canonical Wnt signaling through Vangl2","volume":"125","author":"Bell","year":"2022","journal-title":"Semin Cell Dev Biol"},{"issue":"1","key":"bib44","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1038\/s41392-023-01688-x","article-title":"Ischemia-reperfusion injury: molecular mechanisms and therapeutic targets","volume":"9","author":"Zhang","year":"2024","journal-title":"Signal Transduct Target Ther"},{"issue":"1","key":"bib45","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1016\/j.gendis.2023.01.030","article-title":"Canonical and noncanonical Wnt signaling: multilayered mediators, signaling mechanisms and major signaling crosstalk","volume":"11","author":"Qin","year":"2024","journal-title":"Genes Dis"},{"issue":"1","key":"bib46","doi-asserted-by":"publisher","first-page":"692","DOI":"10.1038\/s42003-021-02223-w","article-title":"Single-cell RNA sequencing of human nail unit defines RSPO4 onychofibroblasts and SPINK6 nail epithelium","volume":"4","author":"Kim","year":"2021","journal-title":"Commun Biol"},{"issue":"4","key":"bib47","doi-asserted-by":"publisher","first-page":"791","DOI":"10.1038\/sj.jid.5701088","article-title":"RSPO4 is the major gene in autosomal-recessive anonychia and mutations cluster in the furin-like cysteine-rich domains of the Wnt signaling ligand R-spondin 4","volume":"128","author":"Br\u00fcchle","year":"2008","journal-title":"J Invest Dermatol"},{"key":"bib48","doi-asserted-by":"publisher","first-page":"119195","DOI":"10.1016\/j.gep.2021.119195","article-title":"Expression of R-spondins\/Lgrs in development of movable craniofacial organs","volume":"41","author":"Nihara","year":"2021","journal-title":"Gene Expr Patterns"},{"key":"bib49","doi-asserted-by":"publisher","first-page":"119333","DOI":"10.1016\/j.gep.2023.119333","article-title":"Spatiotemporal expression patterns of R-spondins and their receptors, Lgrs, in the developing mouse telencephalon","volume":"49","author":"Watanabe","year":"2023","journal-title":"Gene Expr Patterns"},{"issue":"3","key":"bib50","doi-asserted-by":"publisher","first-page":"306","DOI":"10.1016\/j.modgep.2006.08.006","article-title":"Dynamic expression of R-spondin family genes in mouse development","volume":"7","author":"Nam","year":"2007","journal-title":"Gene Expr Patterns"}],"container-title":["Investigative Ophthalmology &amp; Visual Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/iovs.arvojournals.org\/article.aspx?articleid=2802420","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T21:32:12Z","timestamp":1791927132000},"score":1,"resource":{"primary":{"URL":"https:\/\/iovs.arvojournals.org\/article.aspx?articleid=2802420"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,6]]},"references-count":50,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2025,1,2]]}},"URL":"https:\/\/doi.org\/10.1167\/iovs.66.1.8","relation":{},"ISSN":["1552-5783"],"issn-type":[{"value":"1552-5783","type":"print"}],"subject":[],"published":{"date-parts":[[2025,1,6]]}}}