Altered Bone Marrow Niche Forms Central Innate Immune Memory Driving Cardiac Dysfunction

Altered Bone Marrow Niche Forms Central Innate Immune Memory Driving Cardiac Dysfunction | 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 Altered Bone Marrow Niche Forms Central Innate Immune Memory Driving Cardiac Dysfunction Katsuhito Fujiu, Kohsaku Goto, Yukiteru Nakayama, Junichi Sugita, and 13 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6590712/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract We previously showed that heart failure (HF) induces innate immune memory in hematopoietic stem/progenitor cells (HSPCs), which crucially contributes to HF recurrence and impaired stress responses in multiple organs. While bone marrow (BM) niches maintain hematopoietic homeostasis, their role in innate immune memory remains poorly understood, despite their critical function in long-term HSPC regulation. Here, we demonstrate that BM Lepr+ mesenchymal stromal cells (MSCs) influence HSPCs to promote cardiac pathology in HF. Co-transplantation of Lepr+ MSCs from HF mice with healthy HSPCs resulted in proinflammatory macrophage accumulation in the heart and enhanced cardiac remodeling, indicating that MSCs skew HSPC differentiation toward pathological myelopoiesis. Mechanistically, HF reduced heparin-binding EGF-like growth factor (HBEGF) expression in MSCs by diminishing a distinct HBEGF-expressing MSC subpopulation. Interactome analysis revealed suppression of EGF signaling in HSPCs. MSC-specific Hbegf knockdown enhanced cardiac dysfunction after pressure overload. HF also activated the adipogenic program in MSCs, which correlated with depletion of Hbegf+ MSCs. Notably, a HBEGF+ MSC subpopulation exists in human BM, and HF was associated with increased BM adiposity in humans. Our results identify the BM niche as a key regulator of trained immunity and a potential therapeutic target in HF. Biological sciences/Immunology/Innate immune cells/Monocytes and macrophages Health sciences/Cardiology/Cardiovascular biology/Cardiovascular diseases/Heart failure Central Innate Immune Memory Cardiovascular disease Bone marrow niche Skewed differentiation Hematopoietic stem cell Mesenchymal stromal cell Full Text Additional Declarations There is NO Competing Interest. Cite Share Download PDF Status: Under Review 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. 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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-6590712","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":463029038,"identity":"444e88d2-ea9f-45fb-8b80-0ec9e938f8f1","order_by":0,"name":"Katsuhito 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differentiation, Hematopoietic stem cell, Mesenchymal stromal cell","lastPublishedDoi":"10.21203/rs.3.rs-6590712/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6590712/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"We previously showed that heart failure (HF) induces innate immune memory in hematopoietic stem/progenitor cells (HSPCs), which crucially contributes to HF recurrence and impaired stress responses in multiple organs. While bone marrow (BM) niches maintain hematopoietic homeostasis, their role in innate immune memory remains poorly understood, despite their critical function in long-term HSPC regulation. Here, we demonstrate that BM Lepr+ mesenchymal stromal cells (MSCs) influence HSPCs to promote cardiac pathology in HF. Co-transplantation of Lepr+ MSCs from HF mice with healthy HSPCs resulted in proinflammatory macrophage accumulation in the heart and enhanced cardiac remodeling, indicating that MSCs skew HSPC differentiation toward pathological myelopoiesis. Mechanistically, HF reduced heparin-binding EGF-like growth factor (HBEGF) expression in MSCs by diminishing a distinct HBEGF-expressing MSC subpopulation. Interactome analysis revealed suppression of EGF signaling in HSPCs. MSC-specific Hbegf knockdown enhanced cardiac dysfunction after pressure overload. HF also activated the adipogenic program in MSCs, which correlated with depletion of Hbegf+ MSCs. Notably, a HBEGF+ MSC subpopulation exists in human BM, and HF was associated with increased BM adiposity in humans. Our results identify the BM niche as a key regulator of trained immunity and a potential therapeutic target in HF.","manuscriptTitle":"Altered Bone Marrow Niche Forms Central Innate Immune Memory Driving Cardiac Dysfunction","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-29 03:01:45","doi":"10.21203/rs.3.rs-6590712/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-communications","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"NCOMMS","sideBox":"Learn more about [Nature Communications](http://www.nature.com/ncomms/)","snPcode":"","submissionUrl":"https://mts-ncomms.nature.com/","title":"Nature Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Communications","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"63093378-b862-468b-bdcc-29cda6e66ece","owner":[],"postedDate":"May 29th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":49165701,"name":"Biological sciences/Immunology/Innate immune cells/Monocytes and macrophages"},{"id":49165702,"name":"Health sciences/Cardiology/Cardiovascular biology/Cardiovascular diseases/Heart failure"}],"tags":[],"updatedAt":"2026-04-05T08:35:25+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-29 03:01:45","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6590712","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6590712","identity":"rs-6590712","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}