{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T18:59:23Z","timestamp":1790189963160,"version":"4.1.0"},"reference-count":58,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","license":[{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Cardiac fibrosis is defined by the excessive accumulation of ECM (extracellular matrix) material resulting in cardiac tissue scarring and dysfunction. Although it is commonly accepted that myofibroblasts are the major contributors to ECM deposition in cardiac fibrosis, their origin remains controversial. Our group discovered that a subpopulation of resident vascular stem cells residing within the artery adventitia (termed adventitial Sca1+ smooth muscle-derived progenitor cells [AdvSca1-SM]) originates from mature vascular smooth muscle cells through a KLF4 (Kruppel-like factor 4)\u2013dependent in situ reprogramming process. However, the molecular mechanism(s) whereby KLF4 regulates the AdvSca1-SM phenotype remain unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      We leveraged a highly specific AdvSca1-SM cell reporter system, single-cell RNA-sequencing, and spatial transcriptomic approaches to examine the spatiotemporal differentiation trajectory of AdvSca1-SM cells in AngII (angiotensin II) challenged cardiac tissues. To examine the function of KLF4, we compared the cardiac inflammation and fibrotic response of wild-type and AdvSca1-SM\u2013specific\n                      <jats:italic toggle=\"yes\">Klf4<\/jats:italic>\n                      knockout mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      We demonstrate the profibrotic differentiation trajectory of coronary artery\u2013associated AdvSca1-SM cells in cardiac fibrosis, characterized by loss of stemness-related genes, including\n                      <jats:italic toggle=\"yes\">Klf4<\/jats:italic>\n                      , but gain of expression of a profibrotic phenotype. Importantly, these changes were recapitulated in human cardiac hypertrophic tissue, supporting the translational significance of a profibrotic transition of AdvSca1-SM\u2013like cells in human cardiomyopathy. Spatially, AdvSca1-SM cells expand from the adventitia to the cardiac interstitium while exhibiting close association with T cells. AdvSca1-SM cell\u2013specific knockout of\n                      <jats:italic toggle=\"yes\">Klf4<\/jats:italic>\n                      before AngII treatment paradoxically protected against cardiac T-cell inflammation, fibrosis, and systolic dysfunction.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>Overall, our data reveal the contribution of AdvSca1-SM cells to myofibroblasts in the setting of AngII-induced cardiac fibrosis. KLF4 not only maintains the stemness of AdvSca1-SM cells but also orchestrates their response to profibrotic stimuli and interactions with T cells. KLF4 may serve as a therapeutic target in cardiac fibrosis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/atvbaha.126.324849","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T09:00:19Z","timestamp":1787216419000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["KLF4 in Smooth Muscle Cell\u2013Derived Progenitor Cells Is Essential for Angiotensin II\u2013Induced Cardiac Inflammation and Fibrosis"],"prefix":"10.1161","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9892-8784","authenticated-orcid":true,"given":"Sizhao","family":"Lu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-8841-6470","authenticated-orcid":true,"given":"Tysen","family":"Noble","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-0875-008X","authenticated-orcid":true,"given":"Jake","family":"Elkins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6458-4648","authenticated-orcid":true,"given":"Austin J.","family":"Jolly","sequence":"additional","affiliation":[{"name":"Medical Scientist Training Program, University of Colorado School of Medicine, Aurora (A.J.J., 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