{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T13:15:39Z","timestamp":1762866939764,"version":"3.37.3"},"reference-count":45,"publisher":"American Physiological Society","issue":"5","funder":[{"name":"HHS | NIH | National Heart, Lung, and Blood Institute (NHBLI)","award":["HL78825","HL99014"],"award-info":[{"award-number":["HL78825","HL99014"]}]},{"name":"HHS | NIH | National Heart, Lung, and Blood Institute (NHBLI)","award":["HL113530"],"award-info":[{"award-number":["HL113530"]}]},{"name":"HHS | NIH | National Center for Research Resources (NCRR)","award":["RR024489"],"award-info":[{"award-number":["RR024489"]}]},{"name":"U.S. Department of Veterans Affairs (VA)","award":["Prabhu-0001"],"award-info":[{"award-number":["Prabhu-0001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Heart and Circulatory Physiology"],"published-print":{"date-parts":[[2016,11,1]]},"abstract":"<jats:p>Despite expansion of resident cardiac stem cells (CSCs; c-kit<jats:sup>+<\/jats:sup>Lin<jats:sup>\u2212<\/jats:sup>) after myocardial infarction, endogenous repair processes are insufficient to prevent adverse cardiac remodeling and heart failure (HF). This suggests that the microenvironment in post-ischemic and failing hearts compromises CSC regenerative potential. Inflammatory cytokines, such as tumor necrosis factor-\u03b1 (TNF), are increased after infarction and in HF; whether they modulate CSC function is unknown. As the effects of TNF are specific to its two receptors (TNFRs), we tested the hypothesis that TNF differentially modulates CSC function in a TNFR-specific manner. CSCs were isolated from wild-type (WT), TNFR1\u2212\/\u2212, and TNFR2\u2212\/\u2212 adult mouse hearts, expanded and evaluated for cell competence and differentiation in vitro in the absence and presence of TNF. Our results indicate that TNF signaling in murine CSCs is constitutively related primarily to TNFR1, with TNFR2 inducible after stress. TNFR1 signaling modestly diminished CSC proliferation, but, along with TNFR2, augmented CSC resistance to oxidant stress. Deficiency of either TNFR1 or TNFR2 did not impact CSC telomerase activity. Importantly, TNF, primarily via TNFR1, inhibited cardiomyogenic commitment during CSC differentiation, and instead promoted smooth muscle and endothelial fates. Moreover, TNF, via both TNFR1 and TNFR2, channeled an alternate CSC neuroadrenergic-like fate (capable of catecholamine synthesis) during differentiation. Our results suggest that elevated TNF in the heart restrains cardiomyocyte differentiation of resident CSCs and may enhance adrenergic activation, both effects that would reduce the effectiveness of endogenous cardiac repair and the response to exogenous stem cell therapy, while promoting adverse cardiac remodeling.<\/jats:p><jats:p>Listen to this article's corresponding podcast at http:\/\/ajpheart.podbean.com\/e\/tnf-and-cardiac-stem-cell-differentiation\/ .<\/jats:p>","DOI":"10.1152\/ajpheart.00904.2015","type":"journal-article","created":{"date-parts":[[2016,9,3]],"date-time":"2016-09-03T02:58:39Z","timestamp":1472871519000},"page":"H1189-H1201","source":"Crossref","is-referenced-by-count":23,"title":["TNF receptor signaling inhibits cardiomyogenic differentiation of cardiac stem cells and promotes a neuroadrenergic-like fate"],"prefix":"10.1152","volume":"311","author":[{"given":"Tariq","family":"Hamid","sequence":"first","affiliation":[{"name":"Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham and Birmingham Veterans Affairs Medical Center, Birmingham, Alabama; 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