Deconstruction of human age-related cataract capsules defines aging

Deconstruction of human age-related cataract capsules defines aging | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Resource Deconstruction of human age-related cataract capsules defines aging yibo Yu, Qiaomei Tang, Ziyang Tong, Chunmei Fan, Silong Chen, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7580840/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Age-related cataracts (ARC), a disease associated with aging, is the leading cause of blindness worldwide. In 2020, an estimated 94 million people older than 50 years were blind or visually impaired globally due to cataract. However, current treatment strategies remain unsatisfactory, primarily due to the complex and heterogeneous pathogenesis of ARC. To better understand the underlying mechanisms and identify potential therapeutic targets, we generate a comprehensive atlas of age-related cataracts at a single-cell resolution, encompassing three disease states—mild cataract group (Mild), severe cortical cataract group (Severe_C), and severe nuclear cataract group (Severe_N)—with a total of 230,838 lens epithelial cells (LECs) derived from the lens capsules of 554 patients. We found that ARC involves seven distinct lens capsule cell types, with notable differences in cellular composition and functional states across disease severities. Unexpectedly, we discovered that neuronal axonal ingrowth into the lens is associated with cataractogenesis and its progress. All three disease groups showed significant enrichment of the neurotrophic SLIT-ROBO signaling pathway, suggesting a conserved neurogenic involvement in ARC. Furthermore, Cluster 0 exhibited high expression of the neurotrophic factor NRG1, which forms a stable ligand-receptor axis with the ERBB3 receptor on sympathetic neurons. These findings not only reveal the heterogeneity of ARC at the levels of cellular composition and signaling pathways, but also suggest that neuro-lens interactions may play a critical role in cataract development. This provides a new perspective for understanding the pathogenesis of age-related cataracts and offers potential directions for the development of targeted therapies in the future. Biological sciences/Cell biology/Senescence Health sciences/Diseases/Metabolic disorders Full Text Additional Declarations There is NO Competing Interest. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7580840","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Resource","associatedPublications":[],"authors":[{"id":517666719,"identity":"99de5936-9235-4d21-b12c-24c0a52abd54","order_by":0,"name":"yibo Yu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAu0lEQVRIiWNgGAWjYJCCwwwMNgyMDUAWDwla0kjUwgzWxUCsFoMbOYaHCyrO2zPPSGB88LaNQd6cCC0Gh2ecuc3MOCOB2XBuG4PhzgZitPC23WYDamGT5m1jSDA4QJyWczxALey/SdFyQAJkCzNRWiTPPCsA+iXZgLHnYbPknHMShhsIaeE7nrz5c0GFnb1he/LBD2/KbOQJ2qJwgMMAzDBsAEemBAH1QCDfwP4AwiCsdhSMglEwCkYqAACu4EGh+B0yewAAAABJRU5ErkJggg==","orcid":"","institution":"Eye Center, The Second Affiliated Hospital, School of Medicine, Zhejiang University","correspondingAuthor":true,"prefix":"","firstName":"yibo","middleName":"","lastName":"Yu","suffix":""},{"id":517666720,"identity":"3082ec6d-a3da-42cb-9822-f5bdf7d71d46","order_by":1,"name":"Qiaomei Tang","email":"","orcid":"","institution":"Eye Center, The Second Affiliated Hospital, School of Medicine, Zhejiang University","correspondingAuthor":false,"prefix":"","firstName":"Qiaomei","middleName":"","lastName":"Tang","suffix":""},{"id":517666721,"identity":"b7a78292-f3de-44b5-a730-3af7358b7afb","order_by":2,"name":"Ziyang Tong","email":"","orcid":"","institution":"Zhejiang University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Ziyang","middleName":"","lastName":"Tong","suffix":""},{"id":517666722,"identity":"01741edf-7cd6-4558-926f-3b7b4da5ef9b","order_by":3,"name":"Chunmei Fan","email":"","orcid":"","institution":"The Second Affiliated Hospital, Zhejiang University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Chunmei","middleName":"","lastName":"Fan","suffix":""},{"id":517666723,"identity":"7add2d6b-abf5-4e17-a366-0e24f6551eea","order_by":4,"name":"Silong Chen","email":"","orcid":"","institution":"Eye Center, The Second Affiliated Hospital, School of Medicine, Zhejiang University","correspondingAuthor":false,"prefix":"","firstName":"Silong","middleName":"","lastName":"Chen","suffix":""},{"id":517666724,"identity":"0269a215-9ee1-416b-9294-128dfa32c836","order_by":5,"name":"Jiarui Guo","email":"","orcid":"","institution":"Eye Center, The Second Affiliated Hospital, School of Medicine, Zhejiang University","correspondingAuthor":false,"prefix":"","firstName":"Jiarui","middleName":"","lastName":"Guo","suffix":""},{"id":517666725,"identity":"8d3a3b0f-b26e-49f8-a663-08d2970e9cb2","order_by":6,"name":"Jianghua Hu","email":"","orcid":"","institution":"Department of Ophthalmology, Jiande Branch, The Second Affiliated Hospital, School of Medicine, Zhejiang University","correspondingAuthor":false,"prefix":"","firstName":"Jianghua","middleName":"","lastName":"Hu","suffix":""},{"id":517666726,"identity":"5fc113a2-e433-4296-ae68-9004b4d05bc7","order_by":7,"name":"Ke Yao","email":"","orcid":"","institution":"Eye Center, The Second Affiliated Hospital, School of Medicine, Zhejiang University","correspondingAuthor":false,"prefix":"","firstName":"Ke","middleName":"","lastName":"Yao","suffix":""},{"id":517666727,"identity":"a2da14b8-baa5-4192-bffb-04d1d0779d56","order_by":8,"name":"Zi Yin","email":"","orcid":"https://orcid.org/0000-0003-2892-8962","institution":"Zhejiang University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Zi","middleName":"","lastName":"Yin","suffix":""},{"id":517666728,"identity":"3bab2757-7e73-4b13-b41e-4cd14169028c","order_by":9,"name":"Xiao Chen","email":"","orcid":"https://orcid.org/0000-0002-4438-5286","institution":"Zhejiang University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Xiao","middleName":"","lastName":"Chen","suffix":""}],"badges":[],"createdAt":"2025-09-10 08:56:21","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7580840/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7580840/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":92845787,"identity":"10f298c9-5bd0-4b38-a030-4667d119679e","added_by":"auto","created_at":"2025-10-06 09:34:39","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2001146,"visible":true,"origin":"","legend":"","description":"","filename":"0909mergeDeconstructionofhumanagerelatedcataractcapsulesdefinesaging.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7580840/v1_covered_005b773f-a0c1-41a8-9ea0-fc40de5d797b.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Deconstruction of human age-related cataract capsules defines aging","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7580840/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7580840/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Age-related cataracts (ARC), a disease associated with aging, is the leading cause of blindness worldwide. In 2020, an estimated 94 million people older than 50 years were blind or visually impaired globally due to cataract. However, current treatment strategies remain unsatisfactory, primarily due to the complex and heterogeneous pathogenesis of ARC. To better understand the underlying mechanisms and identify potential therapeutic targets, we generate a comprehensive atlas of age-related cataracts at a single-cell resolution, encompassing three disease states—mild cataract group (Mild), severe cortical cataract group (Severe_C), and severe nuclear cataract group (Severe_N)—with a total of 230,838 lens epithelial cells (LECs) derived from the lens capsules of 554 patients. We found that ARC involves seven distinct lens capsule cell types, with notable differences in cellular composition and functional states across disease severities. Unexpectedly, we discovered that neuronal axonal ingrowth into the lens is associated with cataractogenesis and its progress. All three disease groups showed significant enrichment of the neurotrophic SLIT-ROBO signaling pathway, suggesting a conserved neurogenic involvement in ARC. Furthermore, Cluster 0 exhibited high expression of the neurotrophic factor NRG1, which forms a stable ligand-receptor axis with the ERBB3 receptor on sympathetic neurons. These findings not only reveal the heterogeneity of ARC at the levels of cellular composition and signaling pathways, but also suggest that neuro-lens interactions may play a critical role in cataract development. This provides a new perspective for understanding the pathogenesis of age-related cataracts and offers potential directions for the development of targeted therapies in the future.","manuscriptTitle":"Deconstruction of human age-related cataract capsules defines aging","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-22 06:45:16","doi":"10.21203/rs.3.rs-7580840/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9742b166-f198-436e-887d-01a7efd5ea30","owner":[],"postedDate":"September 22nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":55016228,"name":"Biological sciences/Cell biology/Senescence"},{"id":55016229,"name":"Health sciences/Diseases/Metabolic disorders"}],"tags":[],"updatedAt":"2025-10-06T09:26:30+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-22 06:45:16","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7580840","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7580840","identity":"rs-7580840","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}