AD-HIES Fracture Healing Impaired by STAT3 Dysfunction Affecting Stem Cell Mobilization

AD-HIES Fracture Healing Impaired by STAT3 Dysfunction Affecting Stem Cell Mobilization | 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 AD-HIES Fracture Healing Impaired by STAT3 Dysfunction Affecting Stem Cell Mobilization Lingyong Jiang, Qinggang Dai, Xiangru Huang, Zijian Zhang, Siyuan Sun, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6381295/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 Recurrent fractures and delayed fracture healing are key clinical manifestations of autosomal dominant hyper-IgE syndrome (AD-HIES), caused by heterozygous mutations and loss-of-function variants in the signal transducer and activator of transcription 3 (STAT3) gene. However, the precise mechanisms underlying these defects remain unclear, and effective therapies are limited. In this study, we observed significantly delayed healing in pre-osteoblast-specific STAT3 haploinsufficient mice, mirroring the delayed healing seen in patients with AD-HIES. Inducible Col1a2-CreERT2 labels periosteal progenitors and contributes to the majority of chondrocytes and osteoblasts during fracture healing. Conditional STAT3 deficiency in Col1+ cells blocked fracture healing by disrupting endochondral ossification and stem cell mobilization. Single-cell RNA sequencing revealed that STAT3 deficiency reduced the abundance of C-X-C motif ligand 12 (CXCL12) mesenchymal cells, essential for fracture healing. CXCL12 directly enhanced chondrogenic and osteogenic differentiation of STAT3-deficient periosteal cells (PCs) and indirectly promoted vascularization through crosstalk between PCs and human umbilical vein endothelial cells (HUVECs) in vitro. STAT3 directly regulates CXCL12 transcription by promoting promoter activity. Notably, CXCL12 improved fracture healing blocked by complete osteoblast STAT3 deficiency and alleviated delayed healing associated with pre-osteoblast STAT3 haploinsufficiency. Pharmacological STAT3 activation effectively also improved delayed healing and promoted CXCL12 expression. These findings demonstrate that STAT3 dysregulation disrupts endochondral ossification and stem cell mobilization via CXCL12, a promising therapeutic target for improving fracture healing in patients with AD-HIES and other conditions with skeletal fragility. Biological sciences/Stem cells/Mesenchymal stem cells Biological sciences/Physiology/Bone fracture healing STAT3 AD-HIES CXCL12 osteoblast Full Text Additional Declarations There is NO Competing Interest. Supplementary Files NCSUP.docx The Supplementary information includes: Materials and Methods, Supplemental Figure 1 to 2 and Supplementary Table 1. 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-6381295","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":440901772,"identity":"68d7c2c3-d3e5-41c5-aaf1-b02fb4ef8653","order_by":0,"name":"Lingyong 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