title: TNF receptor signaling inhibits cardiomyogenic differentiation of cardiac stem cells and promotes a neuroadrenergic-like fate.
abstract: Despite expansion of resident cardiac stem cells (CSCs; c-kit+Lin-) 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-α (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-/-, and TNFR2-/- 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.
authors: Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham and Birmingham Veterans Affairs Medical Center, Birmingham, Alabama; and.
authors: Tariq
authors: T
authors: Hamid
authors: Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham and Birmingham Veterans Affairs Medical Center, Birmingham, Alabama; and.
authors: Yuanyuan
authors: Y
authors: Xu
authors: Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham and Birmingham Veterans Affairs Medical Center, Birmingham, Alabama; and.
authors: Mohamed Ameen
authors: MA
authors: Ismahil
authors: Department of Medicine, Institute of Molecular Cardiology, Diabetes and Obesity Center, University of Louisville, Louisville, Kentucky.
authors: Qianhong
authors: Q
authors: Li
authors: Department of Medicine, Institute of Molecular Cardiology, Diabetes and Obesity Center, University of Louisville, Louisville, Kentucky.
authors: Steven P
authors: 0000-0001-5376-8089
authors: SP
authors: Jones
authors: Department of Medicine, Institute of Molecular Cardiology, Diabetes and Obesity Center, University of Louisville, Louisville, Kentucky.
authors: Aruni
authors: A
authors: Bhatnagar
authors: Department of Medicine, Institute of Molecular Cardiology, Diabetes and Obesity Center, University of Louisville, Louisville, Kentucky.
authors: Roberto
authors: R
authors: Bolli
authors: Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham and Birmingham Veterans Affairs Medical Center, Birmingham, Alabama; and sprabhu@uab.edu.
authors: Sumanth D
authors: SD
authors: Prabhu
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D024202:Electrophoretic Mobility Shift Assay; D004837:Epinephrine / Q000378:metabolism; D005434:Flow Cytometry; D015151:Immunoblotting; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D009206:Myocardium / Q000166:cytology*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics*; D012038:Regeneration; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D019098:Telomerase / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; D019098:Telomerase; D009638:Norepinephrine; D004837:Epinephrine
keywords: TNF receptor; cardiac stem cell; cell differentiation; tumor necrosis factor