Intravenous Delivery of Mesenchymal Stromal Cells Reverses Müller Cell Endoplasmic Reticulum Stress in Diabetic Retinopathy

Intravenous Delivery of Mesenchymal Stromal Cells Reverses Müller Cell Endoplasmic Reticulum Stress in Diabetic Retinopathy | 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 Research Article Intravenous Delivery of Mesenchymal Stromal Cells Reverses Müller Cell Endoplasmic Reticulum Stress in Diabetic Retinopathy wei yan, Ruiyun Guo, Tong Liu, Yukun Liu, Rui Ping, Boxin Liu, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6169472/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 27 Dec, 2025 Read the published version in Stem Cell Research & Therapy → Version 1 posted 4 You are reading this latest preprint version Abstract Background Mesenchymal stromal cells (MSCs) are being extensively studied as a disease-modifying therapy for complications of diabetes mellitus (DM) such as diabetic retinopathy (DR). However, the optimal treatment regimen remains unclear, and challenges persist regarding the timing and route of administration and the mechanisms underlying its effects. This study aimed to investigate the specific role of human umbilical cord-derived mesenchymal stromal cells(hUC-MSCs) in retinal protection, as well as the mechanisms underlying the effects of a single intravenous injection on the pathological alterations of DR. Methods Two time points after the development of diabetes mellitus were chosen for the in vivo experiments to study the effects of the intervention at different disease stages. hUC-MSCs were injected into the tail vein at the 8th and 16th week after STZ injection, and the samples were collected 2 weeks later to observe the therapeutic effect of MSCs on diabetic eye disease. In vitro experiments were conducted using a Müller cell line cultured in a high-glucose environment with hUC-MSCs conditioned media (MSC-CM) to further explore the mechanism of the observed in vivo results. Results After a single intravenous injection of hUC-MSCs at weeks 8 and 16 post-STZ injection, retinal tissue showed improved thickness, particularly in the inner nuclear layer. MSC treatment reduced activation markers (GFAP and Vimentin) of Műller cells and alleviated endoplasmic reticulum (ER) stress. VEGF expression was also reduced in the Műller cells. In summary, MSC-conditioned medium reversed high glucose-induced ER stress and increased expression of VEGF in Műller cells. Conclusions Intravenous injection of hUC-MSC to diabetic animals can alleviate Műller cell activation and ER stress which might represent a therapeutic target for DR. Diabetic retinopathy Human umbilical cord mesenchymal stromal cells Műller cells endoplasmic reticulum stress Full Text Supplementary Files AuthorChecklistFull.pdf SupplementaryFigureS1.FulllengthblotsofFigure6.pdf Cite Share Download PDF Status: Published Journal Publication published 27 Dec, 2025 Read the published version in Stem Cell Research & Therapy → Version 1 posted Reviewers agreed at journal 22 Mar, 2025 Reviewers invited by journal 22 Mar, 2025 Editor assigned by journal 17 Mar, 2025 First submitted to journal 15 Mar, 2025 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. 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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-6169472","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":432570612,"identity":"9c924bbe-e5dd-453e-abf3-879b360330ef","order_by":0,"name":"wei yan","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA0ElEQVRIiWNgGAWjYNACAwYGNmbmAwc+/CBFCx87W+LBmT2kWCTHz2N8mIONGPOPnz0m8aHATp6NmefDYQYeBnl+sQMEtJzJS5OcYZBs2MbMu+FwgQWD4czZCQS0HMgxu81jwMwI1jKDhyHB4DYhLeffmN3+Y1Bv38bM8+AwDxsxWm4AbWEwOJwI1MJAnBbJG2/Mf/YYHE9uY2YzAAayBGG/8J3PMTb48afadn7/4ccfPvywkeeXJqBF4QAqXwK/chCQbyCsZhSMglEwCkY6AADHb0OJikhOxAAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0009-0003-0101-8683","institution":"Hebei Medical University","correspondingAuthor":true,"prefix":"","firstName":"wei","middleName":"","lastName":"yan","suffix":""},{"id":432570613,"identity":"3e3c26eb-0db6-4827-920a-42d5d754996d","order_by":1,"name":"Ruiyun Guo","email":"","orcid":"","institution":"Hebei Medical University","correspondingAuthor":false,"prefix":"","firstName":"Ruiyun","middleName":"","lastName":"Guo","suffix":""},{"id":432570614,"identity":"ed6bd762-ff3e-4e81-af31-30415727c57e","order_by":2,"name":"Tong Liu","email":"","orcid":"","institution":"Hebei Medical University","correspondingAuthor":false,"prefix":"","firstName":"Tong","middleName":"","lastName":"Liu","suffix":""},{"id":432570615,"identity":"fe0b6066-473c-4b37-ab0f-c0b708d9a0cb","order_by":3,"name":"Yukun Liu","email":"","orcid":"","institution":"Hebei Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yukun","middleName":"","lastName":"Liu","suffix":""},{"id":432570616,"identity":"8fd54089-185f-4218-8a86-f330902c577b","order_by":4,"name":"Rui Ping","email":"","orcid":"","institution":"Hebei Medical University","correspondingAuthor":false,"prefix":"","firstName":"Rui","middleName":"","lastName":"Ping","suffix":""},{"id":432570617,"identity":"1b4489ea-f1b0-4d2c-b0c5-9848ed1351df","order_by":5,"name":"Boxin Liu","email":"","orcid":"","institution":"Hebei Medical University","correspondingAuthor":false,"prefix":"","firstName":"Boxin","middleName":"","lastName":"Liu","suffix":""},{"id":432570618,"identity":"b8e5e585-e8db-4c1b-aaf6-3f95563fa937","order_by":6,"name":"Jingjing He","email":"","orcid":"","institution":"Hebei Medical University","correspondingAuthor":false,"prefix":"","firstName":"Jingjing","middleName":"","lastName":"He","suffix":""},{"id":432570619,"identity":"74202a7a-b0be-4854-b555-1326832f1668","order_by":7,"name":"Matthew D. 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However, the optimal treatment regimen remains unclear, and challenges persist regarding the timing and route of administration and the mechanisms underlying its effects. This study aimed to investigate the specific role of human umbilical cord-derived mesenchymal stromal cells(hUC-MSCs) in retinal protection, as well as the mechanisms underlying the effects of a single intravenous injection on the pathological alterations of DR.\n\nMethods\n\nTwo time points after the development of diabetes mellitus were chosen for the in vivo experiments to study the effects of the intervention at different disease stages. hUC-MSCs were injected into the tail vein at the 8th and 16th week after STZ injection, and the samples were collected 2 weeks later to observe the therapeutic effect of MSCs on diabetic eye disease. In vitro experiments were conducted using a Müller cell line cultured in a high-glucose environment with hUC-MSCs conditioned media (MSC-CM) to further explore the mechanism of the observed in vivo results.\n\nResults\n\nAfter a single intravenous injection of hUC-MSCs at weeks 8 and 16 post-STZ injection, retinal tissue showed improved thickness, particularly in the inner nuclear layer. MSC treatment reduced activation markers (GFAP and Vimentin) of Műller cells and alleviated endoplasmic reticulum (ER) stress. VEGF expression was also reduced in the Műller cells. In summary, MSC-conditioned medium reversed high glucose-induced ER stress and increased expression of VEGF in Műller cells.\n\nConclusions\n\nIntravenous injection of hUC-MSC to diabetic animals can alleviate Műller cell activation and ER stress which might represent a therapeutic target for DR.","manuscriptTitle":"Intravenous Delivery of Mesenchymal Stromal Cells Reverses Müller Cell Endoplasmic Reticulum Stress in Diabetic Retinopathy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-01 05:36:57","doi":"10.21203/rs.3.rs-6169472/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2025-03-22T22:39:26+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-03-22T22:30:08+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-03-17T06:49:12+00:00","index":"","fulltext":""},{"type":"submitted","content":"Stem Cell Research \u0026 Therapy","date":"2025-03-15T07:47:48+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"stem-cell-research-and-therapy","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scrt","sideBox":"Learn more about [Stem Cell Research \u0026 Therapy](http://stemcellres.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/scrt/default.aspx","title":"Stem Cell Research \u0026 Therapy","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a2be2225-a4e6-46b7-b661-704363d23427","owner":[],"postedDate":"April 1st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-12-29T15:59:56+00:00","versionOfRecord":{"articleIdentity":"rs-6169472","link":"https://doi.org/10.1186/s13287-025-04876-4","journal":{"identity":"stem-cell-research-and-therapy","isVorOnly":false,"title":"Stem Cell Research \u0026 Therapy"},"publishedOn":"2025-12-27 15:57:20","publishedOnDateReadable":"December 27th, 2025"},"versionCreatedAt":"2025-04-01 05:36:57","video":"","vorDoi":"10.1186/s13287-025-04876-4","vorDoiUrl":"https://doi.org/10.1186/s13287-025-04876-4","workflowStages":[]},"version":"v1","identity":"rs-6169472","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6169472","identity":"rs-6169472","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}