Liver impairment by senescence is caused by hepatocyte reversal to a CD44high de-differentiation state

Liver impairment by senescence is caused by hepatocyte reversal to a CD44high de-differentiation state | 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 Liver impairment by senescence is caused by hepatocyte reversal to a CD44high de-differentiation state Thomas Brand, Johannes Lehmann, Saskia van Essen - van Dorresteijn, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6172253/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 Loss of tissue homeostasis increases the risk of developing chronic diseases. To maintain integrity, cells in damaged areas can de-differentiate towards progenitors, which then expand, re-differentiate, and restore function. Factors secreted by senescent cells chronically impair tissue homeostasis, but it remains poorly understood how. Here, we show that senescent cells can induce plasticity of neighboring cells into a CD44 high state. In hepatocyte organoids and multicellular iPSC-derived 3D liver structures this results in an IL-1β, IL-6 and IKK-dependent loss of functional biomarkers, such as Albumin and Cyp3A4, and a blocks recovery from physical injury. Importantly, eliminating senescent cells with a compound resistant to liver enzymes and with potent liver uptake, CL04183, counters the CD44 high state and restores hepatocyte differentiation in vitro and in vivo. Thus, senescent cells are a culprit in liver homeostasis, by driving long-term, but reversible, de-differentiation of hepatocytes towards a CD44 high state. Biological sciences/Cell biology/Senescence Biological sciences/Stem cells/Reprogramming Full Text Additional Declarations Table 1 to 8 are available in the Supplementary Files section. Supplementary Files Extratables.pdf 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-6172253","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":427382409,"identity":"c3558ed6-f2a3-4732-b801-11ab47265760","order_by":0,"name":"Thomas 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To maintain integrity, cells in damaged areas can de-differentiate towards progenitors, which then expand, re-differentiate, and restore function. Factors secreted by senescent cells chronically impair tissue homeostasis, but it remains poorly understood how.\u003c/p\u003e\n\u003cp\u003eHere, we show that senescent cells can induce plasticity of neighboring cells into a CD44\u003csup\u003ehigh\u003c/sup\u003e\u0026nbsp;state. In hepatocyte organoids and multicellular iPSC-derived 3D liver structures this results in an IL-1β, IL-6 and IKK-dependent loss of functional biomarkers, such as Albumin and Cyp3A4, and a blocks recovery from physical injury. Importantly, eliminating senescent cells with a compound resistant to liver enzymes and with potent liver uptake, CL04183, counters the CD44\u003csup\u003ehigh\u003c/sup\u003e\u0026nbsp;state and restores hepatocyte differentiation in vitro and in vivo. 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