Improved efficacy of cell-based therapy in a cerebral infarction model by cotreatment with hyaluronan

Improved efficacy of cell-based therapy in a cerebral infarction model by cotreatment with hyaluronan | 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 Article Improved efficacy of cell-based therapy in a cerebral infarction model by cotreatment with hyaluronan Jui-Sheng Chen, Cheng-Chun Wu, Hung-Chih Chen, Yuan-Yuan Cheng, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8574092/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 9 You are reading this latest preprint version Abstract Background Cerebral infarction (ischemic stroke) is a leading cause of morbidity and mortality worldwide. Cell-based therapy has shown some benefits during the acute phase post-stroke, but longer-term efficacy is limited by insufficient expression of cytoprotective, growth-promoting, angiogenic, and immunomodulatory factors. We speculated that cotreatment with hyaluronan would enhance the therapeutic efficacy of bone marrow mononuclear cell (MNC) injection in a mouse stroke model. Methods Mice subjected to middle cerebral artery occlusion (MCAo) were injected with MNCs, hyaluronan, or the combination (HA + MNCs), and subsequently tested for sensorimotor recovery using the neurological severity score (mNSS) test battery, von Frey tactile sensitivity test, and wire-hanging test 3, 5, and 7 days post-MCAo. Results Combined treatment with MNCs plus hyaluronan enhanced focal hyperemia in the acute stage post-MCAo compared to either treatment alone. In addition, combined treatment augmented local angiogenesis, promoted neuronal survival in the ischemic field, reduced infarct size, and improved sensorimotor recovery in the weeks post-MCAo. These beneficial effects were associated with reductions in reactive gliosis and T-cell activation as well as enhanced secretion of anti-inflammatory cytokines. In conclusion, hyaluronan cotreatment may enhance the therapeutic efficacy of cell-based therapy following cerebral infarction. Health sciences/Diseases Health sciences/Medical research Health sciences/Neurology Biological sciences/Neuroscience cerebral infarction hyaluronan mononuclear cells cell therapy inflammation Full Text Additional Declarations No competing interests reported. Supplementary Files Supplementdata.pptx Cite Share Download PDF Status: Under Revision Version 1 posted Editorial decision: Revision requested 31 Mar, 2026 Reviews received at journal 30 Mar, 2026 Reviewers agreed at journal 25 Feb, 2026 Reviews received at journal 10 Feb, 2026 Reviewers agreed at journal 21 Jan, 2026 Reviewers invited by journal 20 Jan, 2026 Editor assigned by journal 19 Jan, 2026 Submission checks completed at journal 19 Jan, 2026 First submitted to journal 11 Jan, 2026 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-8574092","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":578013503,"identity":"9b48ff22-0982-4154-9150-42251f2dc323","order_by":0,"name":"Jui-Sheng Chen","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5UlEQVRIiWNgGAWjYFCCxIYDHwxq7PgZGAyYidSS3PhwRsWxZMkGuBaCOtObjTnOMDNuOECsFn72xDZpxjY2ZuPjzRs/FzDY5Ms78B+TwKdFsudhm3Rhmwyf2ZljxdIzGNIsNx5gZsOrxeAG0JaZQFvMbuQYSPMwHDYwbGBmu4FPiz1IC28bM+Pm+W+MfxOlxUAisdmYB+R9CR4zsC3yDAS0SJx5CAlkiTNpZdY8BmkGBszM5j/waeFvT38Aicr2w5tv81TYGMi3Nz42wKcF3Z1AdJgE9RAg30CyllEwCkbBKBjmAAD1skctbviH6gAAAABJRU5ErkJggg==","orcid":"","institution":"E-DA Hospital","correspondingAuthor":true,"prefix":"","firstName":"Jui-Sheng","middleName":"","lastName":"Chen","suffix":""},{"id":578013504,"identity":"d16c8b87-dcdb-4169-9a79-d1fc133b9717","order_by":1,"name":"Cheng-Chun Wu","email":"","orcid":"","institution":"I-Shou University","correspondingAuthor":false,"prefix":"","firstName":"Cheng-Chun","middleName":"","lastName":"Wu","suffix":""},{"id":578013505,"identity":"0ec02682-aff1-4f5c-aa57-9f7ea1ffd03b","order_by":2,"name":"Hung-Chih Chen","email":"","orcid":"","institution":"Academia Sinica","correspondingAuthor":false,"prefix":"","firstName":"Hung-Chih","middleName":"","lastName":"Chen","suffix":""},{"id":578013506,"identity":"e9deadde-db06-49af-ba02-d2145172c4f7","order_by":3,"name":"Yuan-Yuan Cheng","email":"","orcid":"","institution":"Taipei Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yuan-Yuan","middleName":"","lastName":"Cheng","suffix":""},{"id":578013507,"identity":"ebaf370e-44d7-4295-9bc0-f9ba8319d29b","order_by":4,"name":"Chien-Yu Hsu","email":"","orcid":"","institution":"I-Shou University","correspondingAuthor":false,"prefix":"","firstName":"Chien-Yu","middleName":"","lastName":"Hsu","suffix":""},{"id":578013508,"identity":"fd16749f-074a-4cf4-b6af-de2de7fae5f0","order_by":5,"name":"Kui-Yu Lin","email":"","orcid":"","institution":"Academia Sinica","correspondingAuthor":false,"prefix":"","firstName":"Kui-Yu","middleName":"","lastName":"Lin","suffix":""},{"id":578013509,"identity":"26dc41a0-1bfe-4393-863d-5beca5d83cf5","order_by":6,"name":"Po-Ju Lin","email":"","orcid":"","institution":"Academia Sinica","correspondingAuthor":false,"prefix":"","firstName":"Po-Ju","middleName":"","lastName":"Lin","suffix":""},{"id":578013510,"identity":"dfd3c93b-a79b-4d18-95c0-79dec605919c","order_by":7,"name":"Aij-Lie Kwan","email":"","orcid":"","institution":"Kaohsiung Medical University","correspondingAuthor":false,"prefix":"","firstName":"Aij-Lie","middleName":"","lastName":"Kwan","suffix":""},{"id":578013511,"identity":"bfcc41ad-10ef-4889-9b33-84a2f60f1173","order_by":8,"name":"Patrick C.H. 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hyaluronan","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"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":"npj-regenerative-medicine","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"npjregenmed","sideBox":"Learn more about [npj Regenerative Medicine](http://www.nature.com/npjregenmed/)","snPcode":"41536","submissionUrl":"https://mts-npjregenmed.nature.com/cgi-bin/main.plex","title":"npj Regenerative Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"NPJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"cerebral infarction, hyaluronan, mononuclear cells, cell therapy, inflammation","lastPublishedDoi":"10.21203/rs.3.rs-8574092/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8574092/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eCerebral infarction (ischemic stroke) is a leading cause of morbidity and mortality worldwide. Cell-based therapy has shown some benefits during the acute phase post-stroke, but longer-term efficacy is limited by insufficient expression of cytoprotective, growth-promoting, angiogenic, and immunomodulatory factors. We speculated that cotreatment with hyaluronan would enhance the therapeutic efficacy of bone marrow mononuclear cell (MNC) injection in a mouse stroke model.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eMice subjected to middle cerebral artery occlusion (MCAo) were injected with MNCs, hyaluronan, or the combination (HA\u0026thinsp;+\u0026thinsp;MNCs), and subsequently tested for sensorimotor recovery using the neurological severity score (mNSS) test battery, von Frey tactile sensitivity test, and wire-hanging test 3, 5, and 7 days post-MCAo.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eCombined treatment with MNCs plus hyaluronan enhanced focal hyperemia in the acute stage post-MCAo compared to either treatment alone. In addition, combined treatment augmented local angiogenesis, promoted neuronal survival in the ischemic field, reduced infarct size, and improved sensorimotor recovery in the weeks post-MCAo. These beneficial effects were associated with reductions in reactive gliosis and T-cell activation as well as enhanced secretion of anti-inflammatory cytokines. In conclusion, hyaluronan cotreatment may enhance the therapeutic efficacy of cell-based therapy following cerebral infarction.\u003c/p\u003e","manuscriptTitle":"Improved efficacy of cell-based therapy in a cerebral infarction model by cotreatment with hyaluronan","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-22 19:55:54","doi":"10.21203/rs.3.rs-8574092/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-03-31T12:50:54+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-30T21:48:10+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"289766447718441406429630457581520161062","date":"2026-02-25T09:25:18+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-11T00:40:09+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"253466021928090018557942189196875328077","date":"2026-01-21T07:56:41+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-01-20T18:14:59+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-01-20T00:26:10+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-01-19T05:52:55+00:00","index":"","fulltext":""},{"type":"submitted","content":"npj Regenerative Medicine","date":"2026-01-11T14:12:47+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"npj-regenerative-medicine","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"npjregenmed","sideBox":"Learn more about [npj Regenerative Medicine](http://www.nature.com/npjregenmed/)","snPcode":"41536","submissionUrl":"https://mts-npjregenmed.nature.com/cgi-bin/main.plex","title":"npj Regenerative Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"NPJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"dcaa95e3-be9f-4915-9640-513fc8aa719b","owner":[],"postedDate":"January 22nd, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[{"id":61497061,"name":"Health sciences/Diseases"},{"id":61497062,"name":"Health sciences/Medical research"},{"id":61497063,"name":"Health sciences/Neurology"},{"id":61497064,"name":"Biological sciences/Neuroscience"}],"tags":[],"updatedAt":"2026-03-31T12:57:08+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-22 19:55:54","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8574092","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8574092","identity":"rs-8574092","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}