Stabilisation of HIF signalling in the mouse epicardium extends embryonic potential and neonatal heart regeneration

Stabilisation of HIF signalling in the mouse epicardium extends embryonic potential and neonatal heart regeneration | 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 Stabilisation of HIF signalling in the mouse epicardium extends embryonic potential and neonatal heart regeneration Elisabetta Gamen, Eleanor Price, Daniella Pezzolla, Carla de Villiers, and 11 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2496938/v3 This work is licensed under a CC BY 4.0 License Status: Posted Version 3 posted You are reading this latest preprint version Show more versions Abstract In humans, new-born infants can regenerate their heart during early life. This is modelled in the mouse, where regenerative capacity is maintained for the first week after birth but lost thereafter. Reactivation of this process holds great therapeutic potential; however, the molecular pathways that might be targeted to extend neonatal regeneration remain elusive. Here, we explored a role for hypoxia and HIF signalling on the regulation of epicardial activity in the developing mouse heart and in modulating the response to injury. Hypoxic regions were found in the epicardium from mid-gestation, associating with HIF-1α and HIF-2α, and expression of the epicardial master regulator Wilms’ tumour 1 (WT1). Epicardial deletion of Hif1a reduced WT1 levels, leading to impaired coronary vasculature. Targeting of the HIF degradation enzyme PHD, through pharmacological inhibition with a clinically approved drug or epicardial-specific deletion, stabilised HIF and promoted WT1 activity ex vivo . Finally, a combination of genetic and pharmacological stabilisation of HIF during neonatal heart injury led to prolonged epicardial activation, preservation of myocardium, augmented infarct resolution and preserved function beyond the 7-day regenerative window. These findings suggest modulation of HIF signalling extends epicardial activation to maintain myocardial survival beyond the neonatal regenerative window and may represent a viable strategy for treating ischaemic heart disease. Stem Cell & Developmental Cell Biology Hypoxia heart epicardium development regeneration HIF-1α HIF-2α myocardial infarction EMT WT1 Full Text Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Posted Version 3 posted You are reading this latest preprint version Show more versions 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-2496938","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":519368892,"identity":"d12c7096-283a-4e25-9639-6ad92f4dea79","order_by":0,"name":"Elisabetta Gamen","email":"","orcid":"","institution":"University of Oxford","correspondingAuthor":false,"prefix":"","firstName":"Elisabetta","middleName":"","lastName":"Gamen","suffix":""},{"id":519368893,"identity":"10bec6b7-1331-4fa1-b136-9c87b095336f","order_by":1,"name":"Eleanor Price","email":"","orcid":"","institution":"University of 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This is modelled in the mouse, where regenerative capacity is maintained for the first week after birth but lost thereafter. Reactivation of this process holds great therapeutic potential; however, the molecular pathways that might be targeted to extend neonatal regeneration remain elusive. Here, we explored a role for hypoxia and HIF signalling on the regulation of epicardial activity in the developing mouse heart and in modulating the response to injury. Hypoxic regions were found in the epicardium from mid-gestation, associating with HIF-1α and HIF-2α, and expression of the epicardial master regulator Wilms’ tumour 1 (WT1). Epicardial deletion of \u003cem\u003eHif1a\u003c/em\u003ereduced WT1 levels, leading to impaired coronary vasculature. Targeting of the HIF degradation enzyme PHD, through pharmacological inhibition with a clinically approved drug or epicardial-specific deletion, stabilised HIF and promoted WT1 activity \u003cem\u003eex vivo\u003c/em\u003e. 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