{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T06:16:36Z","timestamp":1792736196909,"version":"4.5.0"},"posted":{"date-parts":[[2025,11,29]]},"group-title":"Cell Biology","reference-count":139,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,11,29]],"date-time":"2025-11-29T00:00:00Z","timestamp":1764374400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,11,27]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>BACKGROUND<\/jats:title>\n                  <jats:p>Abdominal aortic aneurysm (AAA) is characterized by sterile inflammation, immune cell infiltration, and stromal remodeling that progressively weaken the aortic wall, leading to life-threatening aortic rupture. The molecular mechanisms and spatial organization of immune\u2013stromal interactions in human tissue are poorly understood, limiting the potential to develop effective pharmacological therapy for AAA.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>METHODS<\/jats:title>\n                  <jats:p>In this observational cross-sectional study, formalin-fixed, paraffin-embedded tissues from 11 AAA patients and 12 controls were analyzed by Xenium spatial transcriptomics. Cellular states and localization within tissue architecture were mapped to identify cellular neighborhoods and infer cell\u2013cell communication.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>RESULTS<\/jats:title>\n                  <jats:p>\n                    We generated a high-resolution spatial transcriptomics atlas of 581,664 cells in 26 clusters. AAAs showed a significant loss of contractile smooth muscle cells, expansion of pro-angiogenic endothelial subsets, and broad infiltration of immune cells. These inflammatory changes were accompanied by expansion of activated, universal, and\n                    <jats:italic>CXCL12\u207a<\/jats:italic>\n                    adventitial fibroblasts. Spatial transcriptomic analysis revealed fibroblast\u2013immune colocalization and adventitial tertiary lymphoid organs. Inferred signaling pathway analysis identified increased interactions between\n                    <jats:italic>CXCL12<\/jats:italic>\n                    \u207a fibroblasts and\n                    <jats:italic>CXCR4<\/jats:italic>\n                    \u207a T and B cells in the adventitia of AAAs. Fibroblasts that expressed\n                    <jats:italic>CXCL12<\/jats:italic>\n                    had significantly more immune cell neighbors than fibroblasts that did not, suggesting that they serve as stromal hubs for adaptive immune clustering. Genome-wide association analysis linked AAA heritability to fibroblasts, modulated smooth muscle cells, and foamy macrophages.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>CONCLUSION<\/jats:title>\n                  <jats:p>\n                    Our novel high-resolution spatial transcriptomic atlas of human AAAs revealed coordinated pathogenic reprogramming of stromal and immune cells, defined by smooth muscle cell depletion, fibroblast activation, endothelial remodeling, and disproportionate expansion of immune cells. Through\n                    <jats:italic>CXCR4<\/jats:italic>\n                    signaling,\n                    <jats:italic>CXCL12<\/jats:italic>\n                    \u207a fibroblasts serve as central organizers of immune niches, suggesting stromal\u2013immune crosstalk as a therapeutic target in AAA.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>CLINICAL PERSPECTIVES<\/jats:title>\n                  <jats:p>What Is New?<\/jats:p>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>We generated the first subcellular-resolution spatial transcriptomic atlas of human abdominal aortic aneurysm (AAA), with &gt;580,000 cells identified from aortic tissue sections<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>\n                        We identified CXCL12\n                        <jats:sup>+<\/jats:sup>\n                        fibroblasts as central stromal hubs that organize adaptive immune niches through CXCR4-mediated crosstalk with B and T cells\n                      <\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>We discovered that stromal populations carry the strongest genetic enrichment for AAA risk, notably fibroblast and modulated smooth muscle cell populations<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                  <jats:p>What Are The Clinical Implications?<\/jats:p>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>These findings position stromal-immune interactions, particularly the CXCL12-CXCR4 axis, as a potential therapeutic target to slow AAA progression<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>The spatial atlas provides a framework for mechanistic studies and drug-discovery efforts, guiding future interventions aimed at modifying the microenvironment that destabilizes the aneurysmal aortic wall<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.1101\/2025.11.24.690328","type":"posted-content","created":{"date-parts":[[2025,11,29]],"date-time":"2025-11-29T19:00:24Z","timestamp":1764442824000},"source":"Crossref","is-referenced-by-count":1,"title":["Spatial Transcriptomics Reveals\n                  <i>CXCL12<\/i>\n                  \u207a Fibroblasts as Central Immune Organizers through CXCR4 Signaling in Abdominal Aortic Aneurysm"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-9109-2846","authenticated-orcid":false,"given":"Dina","family":"Levy-Lambert","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joel L.","family":"Ramirez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saba","family":"Shaikh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cesar","family":"De Jeronimo Diaz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"April G.","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexis","family":"Combes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriela K.","family":"Fragiadakis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trevor P.","family":"Fidler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam Z.","family":"Oskowitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025120104304167000_2025.11.24.690328v1.1","first-page":"203","article-title":"Screening for abdominal aortic aneurysm: a best-evidence systematic review for the U","volume":"142","year":"2005","journal-title":"S. 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