title: TNF, acting through inducibly expressed TNFR2, drives activation and cell cycle entry of c-Kit+ cardiac stem cells in ischemic heart disease.
abstract: TNF, signaling through TNFR2, has been implicated in tissue repair, a process that in the heart may be mediated by activated resident cardiac stem cells (CSCs). The objective of our study is to determine whether ligation of TNFR2 can induce activation of resident CSCs in the setting of ischemic cardiac injury. We show that in human cardiac tissue affected by ischemia heart disease (IHD), TNFR2 is expressed on intrinsic CSCs, identified as c-kit(+)/CD45(-)/VEGFR2(-) interstitial round cells, which are activated as determined by entry to cell cycle and expression of Lin-28. Wild-type mouse heart organ cultures subjected to hypoxic conditions both increase cardiac TNF expression and show induced TNFR2 and Lin-28 expression in c-kit(+) CSCs that have entered cell cycle. These CSC responses are enhanced by exogenous TNF. TNFR2(-/-) mouse heart organ cultures subjected to hypoxia increase cardiac TNF but fail to induce CSC activation. Similarly, c-kit(+) CSCs isolated from mouse hearts exposed to hypoxia or TNF show induction of Lin-28, TNFR2, cell cycle entry, and cardiogenic marker, α-sarcomeric actin (α-SA), responses more pronounced by hypoxia in combination with TNF. Knockdown of Lin-28 by siRNA results in reduced levels of TNFR2 expression, cell cycle entry, and diminished expression of α-SA. We conclude that hypoxia-induced c-kit(+) CSC activation is mediated by TNF/TNFR2/Lin-28 signaling. These observations suggest that TNFR2 signaling in resident c-kit(+) CSCs induces cardiac repair, findings which provide further understanding of the unanticipated harmful effects of TNF blockade in human IHD.
authors.affiliation: Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom.
authors.forename: Rafia S
authors.initials: RS
authors.lastname: Al-Lamki
authors.forename: Wanhua
authors.initials: W
authors.lastname: Lu
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Sargeant
authors.forename: Richard
authors.initials: R
authors.lastname: Wells
authors.forename: Chenqu
authors.initials: C
authors.lastname: Suo
authors.forename: Penny
authors.initials: P
authors.lastname: Wright
authors.forename: Martin
authors.initials: M
authors.lastname: Goddard
authors.forename: Qunhua
authors.initials: Q
authors.lastname: Huang
authors.forename: Amir H
authors.initials: AH
authors.lastname: Lebastchi
authors.forename: George
authors.initials: G
authors.lastname: Tellides
authors.forename: Yingqun
authors.initials: Y
authors.lastname: Huang
authors.forename: Wang
authors.initials: W
authors.lastname: Min
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Pober
authors.forename: John R
authors.initials: JR
authors.lastname: Bradley
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D002469:Cell Separation; D005455:Fluorescent Antibody Technique; D006801:Humans; D017403:In Situ Hybridization; D017493:Leukocyte Common Antigens / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000473:pathology*; D009206:Myocardium / Q000473:pathology*; D009924:Organ Culture Techniques; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D000199:Actins; C000715187:Lin28A protein, human; D016601:RNA-Binding Proteins; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D019009:Proto-Oncogene Proteins c-kit; D040301:Vascular Endothelial Growth Factor Receptor-2; D017493:Leukocyte Common Antigens
keywords: c-kit+CSCs TNFR2 Tumor necrosis factor Lin-28 Hypoxia